U.S. patent application number 09/904114 was filed with the patent office on 2002-03-07 for n-(4-sulfonylaryl)cyclylamine 2-hydroxyethylamines as beta-3 adrenergic receptor agonists.
This patent application is currently assigned to American Home Products Corporation. Invention is credited to Malamas, Michael S., Sum, Fuk-Wah.
Application Number | 20020028797 09/904114 |
Document ID | / |
Family ID | 22815690 |
Filed Date | 2002-03-07 |
United States Patent
Application |
20020028797 |
Kind Code |
A1 |
Sum, Fuk-Wah ; et
al. |
March 7, 2002 |
N-(4-sulfonylaryl)Cyclylamine 2-hydroxyethylamines as beta-3
adrenergic receptor agonists
Abstract
This invention provides compounds of Formula I having the
structure 1 wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, W, X, and Y
are as defined hereinbefore or a pharmaceutically acceptable salt
thereof, which are useful in treating metabolic disorders related
to insulin resistance or hyperglycemia.
Inventors: |
Sum, Fuk-Wah; (Pomona,
NY) ; Malamas, Michael S.; (Jamison, PA) |
Correspondence
Address: |
Steven R. Eck
American Home Products Corporation
Patent Law Department - 2B
Five Giralda Farms
Madison
NJ
07940
US
|
Assignee: |
American Home Products
Corporation
Madison
NJ
|
Family ID: |
22815690 |
Appl. No.: |
09/904114 |
Filed: |
July 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60218589 |
Jul 17, 2000 |
|
|
|
Current U.S.
Class: |
514/210.01 ;
514/217.11; 514/317; 514/426; 540/605; 546/223; 548/557;
548/953 |
Current CPC
Class: |
A61P 29/00 20180101;
A61P 13/00 20180101; C07D 401/12 20130101; C07D 417/14 20130101;
A61P 3/10 20180101; C07D 211/58 20130101; C07D 401/14 20130101 |
Class at
Publication: |
514/210.01 ;
514/217.11; 514/317; 514/426; 540/605; 546/223; 548/953;
548/557 |
International
Class: |
A61K 031/445; A61K
031/55; A61K 031/397; A61K 031/40 |
Claims
What is claimed is:
1. A compound of formula I having the structure 12wherein: W is
(CH.sub.2).sub.m; X is (CH.sub.2).sub.n; Y is OCH.sub.2, SCH.sub.2,
or a bond; R.sub.1 is phenyl substituted with R.sub.5 and R.sub.6,
or Het substituted with R.sub.5 and R.sub.6; R.sub.2 is hydrogen,
trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon
atoms, or alkynyl of 2-7 carbon atoms; R.sub.4 is alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted
with R.sub.5 and R.sub.6, Het substituted with R.sub.5 and R.sub.6,
aryloxy, --NHCOR.sub.7, --NR.sub.8R.sub.8,
--CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino, arylalkylamino
having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having
1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13
carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl
of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in
the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the
alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms,
alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain,
phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6
carbon atoms; R.sub.3, R.sub.5, and R.sub.6, are each,
independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon
atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,
cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6
carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms
in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6
carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the
alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein R.sub.2 is hydrogen;
R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms, aryl
substituted with R.sub.4 and R.sub.5, Het substituted with R.sub.5
and R.sub.6, --NR.sub.8R.sub.8, or --CR.sub.3R.sub.5R.sub.6;
R.sub.3, R.sub.5, and R.sub.6 are each, independently, hydrogen,
alkyl of 1-6 carbon atoms, alkenyl fo 2-7 carbon atoms, alkynyl of
2-7 carbon atoms, halogen, hydroxy, alkoxy of 1-6 carbon atoms,
arylalkoxy having 1-6 carbon atoms in the alkyl chain, hydroxy,
arylalkyl having 1-6 carbon atoms in the alkyl chain, Het-alkyl
having 1-6 carbon atoms in the alkyl chain, --NHCOR.sub.7,
--NHSO.sub.2R.sub.7, --NR.sub.8R.sub.8, --COR.sub.8, formylalkyl of
2-7 carbon atoms, or alkoxycarbonylalkyl of 3-13 carbon atoms, or
R.sub.5 and R.sub.6 may be alkylene groups that are taken together
to form a 3-8 membered cycloalkyl ring when R.sub.5 and R.sub.6 are
attached to a common carbon atom; Het is (a) a 6-membered
saturated, partially unsaturated, or unsaturated heterocycle
containing 1-2 nitrogens, optionally fused to a phenyl ring; (b) a
5-membered saturated, partially saturated, or unsaturated
heterocycle containing 1-3 nitrogen, oxygen, or sulfur atoms,
optionally fused to a phenyl ring; (c) a saturated, partially
unsaturated, or unsaturated bicyclic heterocycle containing 1-4
nitrogen, oxygen, or sulfur atoms; (d) carbazole, dibenzofuran, and
dibenzothiophene; wherein one or more of the ring carbon atoms of
Het as described in (a), (b), or (c) may be a carbonyl moiety,
where the ring does not contain a double bond in the position
corresponding to that carbon atom; or a pharmaceutically acceptable
salt thereof.
3. The compound of claim 2, wherein Y is OCH.sub.2 or a bond;
R.sub.2 is hydrogen; R.sub.4 is aryl substituted with R.sub.4 and
R.sub.5, Het substituted with R.sub.5 and R.sub.6,
--NR.sub.8R.sub.8, or --CR.sub.3R.sub.5R.sub.6; R.sub.3, R.sub.5,
and R.sub.6 are each, independently, hydrogen, alkyl of 1-6 carbon
atoms, alkenyl fo 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,
halogen, hydroxy, alkoxy of 1-6 carbon atoms, arylalkoxy having 1-6
carbon atoms in the alkyl chain, hydroxy, --NHSO.sub.2R.sub.7,
--NR.sub.8R.sub.8, --COR.sub.8, formylalkyl of 2-7 carbon atoms, or
alkoxycarbonylalkyl of 3-13 carbon atoms, or R.sub.5 and R.sub.6
may be alkylene groups that are taken together to form a 3-8
membered cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a
common carbon atom; Het is pyridine, pyrimidine, furan, imidazolyl,
thiazole, oxazole, isoxazole, pyrazole, triazole, tetrazole,
carbazole, pyrrole, thiophene, imidazole, imidazol-2-one,
imidazole-2-thione, imidazolidine-2,4-dione, pyrazoline, triazole,
tetrazole, oxazolone, oxadiazole, imidazolone, thiazole,
thiazolone, thiadiazole, thiadiazolone, thiazoladine-2,4-dione,
pyridine, pyrimidine, piperazine, pyrazine, pyrrolidine,
piperidine, morpholine, benzofuran, dibenzofuran, dibenzothiophene,
isobenzofuran, indole, isoindole, benzothiophene,
1,3,-dihydrobenzoimidazol-2-one, benzo[1,2,5]thiadoazole,
2-oxo-2,3-dihydro-1H-benzoimidazole, quinoline, or isoquinoline; or
a pharmaceutically acceptable salt thereof.
4. The compound of claim 1, which is a)
N-Benzyl-N-(3,4-dimethoxy-phenyl)--
4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino-
]-piperidin-1-yl}-benzenesulfonamide; b)
N-Benzyl-N-butyl-4-{4-[(2S)-2-hyd-
roxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-
-1-yl}-benzenesulfonamide; c)
N-Benzyl-N-butyl-4-{4-[2-hydroxy-2-(4-hydrox-
y-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfon-
amide; d)
N-Benzyl-4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-
-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide; e)
N-Benzyl-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethy-
lamino]-piperidin-1-yl}-benzenesulfonamide; f)
N-Benzyl-4-{4-[(2S)-2-hydro-
xy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
g)
N-(3,4-Dimethoxy-phenyl)-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H--
benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
h)
N-(3,4-Dimethoxy-phenyl)-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylam-
ino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide; i)
4-{4-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperidin-1-;
j) yl}-N-(3,4-dimethoxy-phenyl)-benzenesulfonamide; k)
4-{4-[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxy-propylamino]-piperidin-1-yl}-
-N-(3,4-dimethoxy-phenyl)-benzenesulfonamide; l)
N-(3,4-Dimethoxy-phenyl)--
4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-piperidin-1-yl}-be-
nzenesulfonamide; m)
N-Butyl-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H--
benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
n)
N-Butyl-4-{4-[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamino]piperidi-
n-1-yl}-benzenesulfonamide; o)
N-Butyl-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-
-methanesulfonylaminophenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamid-
e; p)
1-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)ethyla-
mino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid isopropyl ester; q)
1-(4-{4-[2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimida-
zol-4-yloxy)propylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-ca-
rboxylic acid isopropyl ester; r)
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dih-
ydro-1H-benzoimidazol-4-yloxy)propylamino]-piperidin-1-yl}-benzenesulfonyl-
)-pyrrolidine-2-carboxylic acid methylamide; s)
1-(4-{4-[2-Hydroxy-2-(4-hy-
droxy-3-methanesulfonylamino-phenyl)ethylamino]-piperidin-1-yl}-benzenesul-
fonyl)-pyrrolidine-2-carboxylic acid; t)
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-
-hydroxy-3-methanesulfonylaminophenyl)-ethylamino]piperidin-1-yl}-benzenes-
ulfonyl)-amino]-acetic acid benzyl ester; u)
[Butyl-(4-{4-[(2R)-2-hydroxy--
2-(4-hydroxy-3-methanesulfonylaminophenyl)-ethylamino]-piperidin-1-yl}-ben-
zenesulfonyl)-amino]-acetic acid; v)
(2R)-1-(4-{4-[(2R)-2-Hydroxy-2-(4-hyd-
roxy-3-methanesulfonylamino-phenyl)ethylamino)-piperidin-1-yl}-benzenesulf-
onyl)-pyrrolidine-2-carboxylic acid benzyl ester; w)
(2S)-1-(4-{4-[2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)et-
hylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid benzyl ester; x)
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfo-
nylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-aceti-
c acid ethyl ester-1-yl}-phenyl)-amino]-acetic acid; y)
N-(2-Hydroxyethyl)-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylami-
no-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide; z)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethyla-
mino]-piperidin-1-yl}-benzenesulfonyl)-methyl-amino]-acetic acid
ethyl ester; aa)
N-Cyclopropylmethyl-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methan-
esulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
bb)
4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethylami-
no]-piperidin-1-yl}-N-isobutyl-benzenesulfonamide; cc)
[Cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylam-
ino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid ethyl ester; dd)
4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonyl-
amino-phenyl)-ethylamino]-piperidin-1-yl}-N-isopropyl-benzenesulfonamide;
ee)
1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-e-
thylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-(2R)-2-carboxylic
acid ethyl ester; ff)
[Cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydro-
xy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfo-
nyl)-amino]-acetic acid; gg)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methane-
sulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-isobuty-
l-amino]-acetic acid ethyl ester; hh)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy--
3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl-
)-methyl-amino]-acetic acid; ii)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-met-
hanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-iso-
butyl-amino]-acetic acid; jj)
1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-metha-
nesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrro-
lidine-(2R)-2-carboxylic acid; kk)
ethyl(2S)-1-[(4-{4-[((2R)-2-hydroxy-2-{-
4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}pheny-
l)sulfonyl]-2-pyrrolidinecarboxylate; ll)
ethyl(2S)-2-{[(4-{4-[((2R)-2-hyd-
roxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidin-
yl}phenyl)sulfonyl]amino}-4-methylpentanoate; mm)
ethyl(2S)-2-{[(4-{4-[((2-
R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-p-
iperidinyl}phenyl)sulfonyl]amino}-3-methylbutanoate; nn)
(2S)-1-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phen-
yl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-2-pyrrolidinecarboxylic
acid; oo) ethyl
1-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-nyl}phenyl)sulf-
onyl]amino}cyclopentanecarboxylate; pp)
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-(-
{1-[4-(1-pyrrolidinylsulfonyl)phenyl]-4-lidinylsulfonyl)phenyl]-4-piperidi-
nyl}amino)ethyl]phenyl}methanesulfonamide; qq)
N-{2-hydroxy-5-[(1R)-1-hydr-
oxy-2-({1-[4-(1-piperidinylsulfonyl)phenyl]-4-idinylsulfonyl)phenyl]-4-pip-
eridinyl}amino)ethyl]phenyl}methanesulfonamide; rr) Ethyl
1-{[(4-(4-[((2R)-2-hydroxy-2-{4-hydroxy-3-inyl}phenyl)sulfonyl]amino}cycl-
ohexanecarboxylate; ss) Ethyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-idin-
yl}phenyl)sulfonyl](isopropyl)amino]acetate; tt)
N-[2-Hydroxy-5-(1-hydroxy-
-2-{1-[4-(toluene-4-sulfonyl)-phenyl]-piperidin-4-ylamino}-ethyl)-phenyl]--
methanesulfonamide; uu)
4-((2S)-2-Hydroxy-3-{1-[4-(toluene-4-sulfonyl)-phe-
nyl]-piperidin-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;
vv)
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)a-
mino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-4-hexynoicacid
tert-butyl ester; ww)
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydrox-
y-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfo-
nyl]-4-hexynoic acid; xx)
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H--
benzoimidazol-4-yloxy)propylamino]-piperidin-1-yl}-benzenesulfonyl)-imidaz-
olidine-2,4-dione; yy)
N-[5-((1R)-2-{1-[4-(2,4-Dioxo-imidazolidine-1-sulfo-
nyl)-phenyl]piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methan-
esulfonamide; zz)
1-(4-{4-[((2S)-2-Hydroxy-2-(2-trifluoromethyl-thiazol-4--
yl)-ethylamino]-piperidin-1-yl)-benzenesulfonyl)-imidazolidine-2,4-dione;
aaa) tert-Butyl
2-{[(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methylsulfony-
l)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate;
bbb)
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phe-
nyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetic acid;
ccc) tert-Butyl
2-{[2-(tert-butoxy)-2-oxoethyl][(4-{4-[((2R)-2-hydroxy-2-{4-hy-
droxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)su-
lfonyl]amino}acetate; ddd)
2-{(Carboxymethyl)[(4-{4-[((2R)-2-hydroxy-2-{4--
hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)-
sulfonyl]amino}acetic acid; eee) Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hyd-
roxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sul-
fonyl]amino}acetate; fff) Methyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-
-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-
amino}acetate; ggg) Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(meth-
ylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]amino}a-
cetylcarbamate; hhh) tert-Butyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3[(m-
ethylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl](met-
hoxycarbonyl)amino]acetate; iii)
[[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[-
(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl](m-
ethoxycarbonyl)amino]acetic acid; jjj) Ethyl
{(2,5-difluorobenzyl)[(4-{4-[-
((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]p-
iperidin-1-yl}phenyl)sulfonyl]amino}acetate; kkk)
1-[4-({[(Butylamino)carb-
onyl]amino}sulfonyl)phenyl]-4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulf-
onyl)amino]phenyl}ethyl)amino]piperidine; lll)
2-{(2,5-Difluorobenzyl)[(4--
{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)ami-
no]-1-piperidinyl}phenyl)sulfonyl]amino}acetic acid; mmm) Ethyl
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}e-
thyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}acetate;
nnn)
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}-
ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}acetic
acid; ooo)
N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[(1-{4-[(4-methylpiperazin-1-yl)sul-
fonyl]phenyl}piperidin-4-yl)amino]ethyl}phenyl)methanesulfonamide;
ppp) tert-Butyl
{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(-
methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]ami-
no}acetate; or a pharmaceutically acceptable salt thereof; and
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-phenyl}-
ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}acetic
acid, sodium salt.
5. A method of treating metabolic disorders mediated by insulin
resistance or hyperglycemia in a mammal in need thereof which
comprises providing to said mammal, an effective amount of a
compound of formula I having the structure 13wherein: W is
(CH.sub.2).sub.m; X is (CH.sub.2).sub.n; Y is OCH.sub.2, SCH.sub.2,
or a bond; R.sub.1 is phenyl substituted with R.sub.5 and R.sub.6,
or Het substituted with R.sub.5 and R.sub.6; R.sub.2 is hydrogen,
trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon
atoms, or alkynyl of 2-7 carbon atoms; R.sub.4 is alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl substituted
with R.sub.5 and R.sub.6, Het substituted with R.sub.5 and R.sub.6,
aryloxy, --NHCOR.sub.7, --NR.sub.8R.sub.8,
--CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino, arylalkylamino
having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having
1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13
carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl
of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in
the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the
alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms,
alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain,
phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6
carbon atoms; R.sub.3, R.sub.5, and R.sub.6, are each,
independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon
atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,
cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6
carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms
in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6
carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the
alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9 (CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
6. A method of treating or inhibiting type II diabetes in a mammal
in need thereof which comprises providing to said mammal, an
effective amount of a compound of Formula I having the structure
14wherein: W is (CH.sub.2).sub.m; X is (CH.sub.2).sub.n; Y is
OCH.sub.2, SCH.sub.2, or a bond; R.sub.1 is phenyl substituted with
R.sub.5 and R.sub.6, or Het substituted with R.sub.5 and R.sub.6;
R.sub.2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms,
alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms,
hydroxy, aryl substituted with R.sub.5 and R.sub.6, Het substituted
with R.sub.5 and R.sub.6, aryloxy, --NHCOR.sub.7,
--NR.sub.8R.sub.8, -CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino,
arylalkylamino having 1-6 carbon atoms in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; R.sub.3, R.sub.5, and R.sub.6,
are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having
1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon
atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of
1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in
the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
7. A method of modulating glucose levels in a mammal in need
thereof which comprises providing to said mammal, an effective
amount of a compound of formula I having the structure 15wherein: W
is (CH.sub.2).sub.m; X is (CH.sub.2).sub.n; Y is OCH.sub.2,
SCH.sub.2, or a bond; R.sub.1 is phenyl substituted with R.sub.5
and R.sub.6, or Het substituted with R.sub.5 and R.sub.6; R.sub.2
is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of
2-7 carbon atoms, or alkynyl of 2-7 carbon atoms; R.sub.4 is alkyl
of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7
carbon atoms, cycloalkyl of 3-8 carbon atoms, hydroxy, aryl
substituted with R.sub.5 and R.sub.6, Het substituted with R.sub.5
and R.sub.6, aryloxy, --NHCOR.sub.7, --NR.sub.8R.sub.8,
-CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino, arylalkylamino
having 1-6 carbon atoms in the alkyl chain, Het-alkylamino having
1-6 carbon atoms in the alkyl chain, alkoxycarbonylalkyl of 3-13
carbon atoms, carboxyalkyl of 2-7 carbon atoms, alkylcarbonylalkyl
of 3-13 carbon atoms, arylcarbonylalkyl having 1-6 carbon atoms in
the alkyl chain, Het-carbonylalkyl having 1-6 carbon atoms in the
alkyl chain, aminocarbonylalkyl of 2-7 carbon atoms,
alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminosulfonylalkyl having 1-6 carbon atoms in the alkyl chain,
phosphonylalkyl of 1-6 carbon atoms, or phosphorylalkyl of 1-6
carbon atoms; R.sub.3, R.sub.5, and R.sub.6, are each,
independently, hydrogen, trifluoromethyl, alkyl of 1-6 carbon
atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms,
cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having 1-6
carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon atoms
in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of 1-6
carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in the
alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
8. A method of treating or inhibiting urinary incontinence in a
mammal in need thereof which comprises providing to said mammal an
effective amount of a compound of formula I having the structure
16wherein: W is (CH.sub.2).sub.m; X is (CH.sub.2).sub.n; Y is
OCH.sub.2, SCH.sub.2, or a bond; R.sub.1 is phenyl substituted with
R.sub.5 and R.sub.6, or Het substituted with R.sub.5 and R.sub.6;
R.sub.2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms,
alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms,
hydroxy, aryl substituted with R.sub.5 and R.sub.6, Het substituted
with R.sub.5 and R.sub.6, aryloxy, --NHCOR.sub.7,
--NR.sub.8R.sub.8, -CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino,
arylalkylamino having 1-6 carbon atoms in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; R.sub.3, R.sub.5, and R.sub.6,
are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having
1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon
atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of
1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in
the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
9. A method of treating or inhibiting atherosclerosis,
gastrointestinal disorders, neurogenic inflammation, glaucoma, or
ocular hypertension in a mammal in need thereof, which comprises
providing to said mammal an effective amount of a compound of
formula I having the structure 17wherein: W is (CH.sub.2).sub.m; X
is (CH.sub.2).sub.n; Y is OCH.sub.2, SCH.sub.2, or a bond; R.sub.1
is phenyl substituted with R.sub.5 and R.sub.6, or Het substituted
with R.sub.5 and R.sub.6; R.sub.2 is hydrogen, trifluoromethyl,
alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl
of 2-7 carbon atoms; R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
Het substituted with R.sub.5 and R.sub.6, aryloxy, --NHCOR.sub.7,
--NR.sub.8R.sub.8, -CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino,
arylalkylamino having 1-6 carbon atoms in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; R.sub.3, R.sub.5, and R.sub.6,
are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having
1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon
atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of
1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in
the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
10. A method of increasing the lean meat to fat ratio in a mammal
in need thereof, which comprises providing to said mammal an
effective amount of a compound of formula I having the structure
18wherein: W is (CH.sub.2).sub.m; X is (CH.sub.2).sub.n; Y is
OCH.sub.2, SCH.sub.2, or a bond; R.sub.1 is phenyl substituted with
R.sub.5 and R.sub.6, or Het substituted with R.sub.5 and R.sub.6;
R.sub.2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms,
alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon atoms;
R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms,
hydroxy, aryl substituted with R.sub.5 and R.sub.6, Het substituted
with R.sub.5 and R.sub.6, aryloxy, --NHCOR.sub.7,
--NR.sub.8R.sub.8, --CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino,
arylalkylamino having 1-6 carbon atoms in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; R.sub.3, R.sub.5, and R.sub.6,
are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having
1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon
atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of
1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in
the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition which comprises a compound of
formula I having the structure 19wherein: W is (CH.sub.2).sub.m; X
is (CH.sub.2).sub.n; Y is OCH.sub.2, SCH.sub.2, or a bond; R.sub.1
is phenyl substituted with R.sub.5 and R.sub.6, or Het substituted
with R.sub.5 and R.sub.6; R.sub.2 is hydrogen, trifluoromethyl,
alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon atoms, or alkynyl
of 2-7 carbon atoms; R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl
of 2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
Het substituted with R.sub.5 and R.sub.6, aryloxy, --NHCOR.sub.7,
--NR.sub.8R.sub.8, --CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino,
arylalkylamino having 1-6 carbon atoms in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; R.sub.3, R.sub.5, and R.sub.6,
are each, independently, hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, alkenyl of 2-7 carbon atoms, alkynyl of 2-7 carbon
atoms, cycloalkyl of 3-8 carbon atoms, aryl, Het, arylalkyl having
1-6 carbon atoms in the alkyl chain, Het-alkyl having 1-6 carbon
atoms in the alkyl chain, halogen, cyano, nitro, hydroxy, alkoxy of
1-6 carbon atoms, aryloxy, arylalkyloxy having 1-6 carbon atoms in
the alkyl chain, alkylthio 1-6 carbon atoms, arylthio, arylamino,
Het-amino, arylalkylamino of 1-6 carbons in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
hydroxyamino, --NHCOR.sub.7, --NHSO.sub.2R.sub.7,
--NHP(O)(R.sub.7).sub.2, --COR.sub.8, --SO.sub.2R.sub.8,
--NR.sub.8R.sub.8, carboxy, alkylcarbonyl of 2-7 carbon atoms,
formylalkyl of 2-7 carbon atoms, phosphoryl, alkoxycarbonylalkyl of
3-13 carbon atoms, carboxyalkyl of 2-7 carbon atoms,
alkylcarbonylalkyl of 2-13 carbon atoms, arylcarbonylalkyl having
1-6 carbon atoms in the alkyl chain, Het-carbonylalkyl having 1-6
carbon atoms in the alkyl chain, aminocarbonylalkyl of 2-7 carbon
atoms, alkylaminocarbonylalkyl of 3-13 carbon atoms,
arylaminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-aminocarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminosulfonylalkyl of 1-6 carbon atoms, alkylsulfonylalkyl of 2-12
carbon atoms, arylsulfonylalkyl having 1-6 carbon atoms in the
alkyl chain, alkylaminosulfonylalkyl of 2-12 carbon atoms,
arylaminosulfonylalkyl of 1-6 carbon atoms, Het-aminosulfonylalkyl
of 1-6 carbon atoms, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms; or R.sub.5 and R.sub.6 may be
alkylene groups that are taken together to form a 3-8 membered
cycloalkyl ring when R.sub.5 and R.sub.6 are attached to a common
carbon atom; R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6
carbon atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon
atoms, --NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of 1-6
carbon atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6,
arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9; R.sub.9 is hydrogen, hydroxy, alkyl of
1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6
carbon atoms, aryl substituted with R.sub.5 and R.sub.6, Het
substituted with R.sub.5 and R.sub.6, arylalkoxy having 1-6 carbon
atoms in the alkyl chain, or --NR.sub.10R.sub.10; R.sub.10 is
hydrogen, alkyl of 1-6 carbon atoms, alkoxycarbonyl of 2-7 carbon
atoms, hydroxy, aryl substituted with R.sub.5 and R.sub.6, or Het
substituted with R.sub.5 and R.sub.6; Het is a monocyclic or
bicyclic heterocycle of 5-10 ring atoms, having 1-4 heteroatoms
selected from oxygen, nitrogen, and sulfur; wherein the heterocycle
may be saturated, unsaturated, or partially unsaturated; and may be
optionally fused to a phenyl ring; m is 1-3; n is 1-3; p is 0-6; or
a pharmaceutically acceptable salt thereof.
Description
[0001] This application claims the benefit of U.S. Provisional
Application No. 60/218,589, filed Jul. 17, 2000.
BACKGROUND OF THE INVENTION
[0002] This invention relates to N-(4-sulfonylaryl)cyclylamine
2-hydroxyethylamine derivatives which are .beta..sub.3 adrenergic
receptor agonists useful for the treatment of metabolic disorders
related to insulin resistance or hyperglycemia (typically
associated with obesity or glucose intolerance), atherosclerosis,
gastrointestinal disorders, neurogenetic inflammation, glaucoma,
ocular hypertension, and and frequent urination, and are
particularly useful in the treatment or inhibition of type II
diabetes.
[0003] The subdivision of .beta. adrenergic receptors (.beta.-AR)
into .beta..sub.1- and .beta..sub.2-AR has led to the development
of .beta..sub.1- and .beta..sub.2-antagonists and/or agonists which
have been useful for the treatment of cardiovascular disease and
asthma. The recent discovery of "atypical" receptors, later called
.beta..sub.3-AR, has led to the development of .beta..sub.3-AR
agnoists which may be potentially useful as antiobesity and
antidiabetic agents. For recent reviews on .beta..sub.3-AR agnoists
, see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37,
421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P.
Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer,
J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25,
11.
[0004] Compounds that are potent and selective .beta..sub.3
agonists, may be potentially useful antiobesity agents. Low levels
or lack of .beta..sub.1 and .beta..sub.2-agonistic properties will
minimize or eliminate the adverse side effects that are associated
with .beta..sub.1 and .beta..sub.2 agonistic activities, i.e.
increased heart rate, and muscle tremor, respectively.
[0005] Early developments in the .beta..sub.3-agonist field are
described in European patent 427480, U.S. Pat. Nos. 4,396,627,
4,478,849, 4,999,377, 5,153,210. Although the early developments
purport to claim compounds with greater .beta..sub.3-AR selectivity
over the .beta..sub.1- and .beta..sub.2-AR. However, clinical
trials in humans with those early developed .beta..sub.3-agonists
have, so far, not been successful.
[0006] More recently, potent and selective human .beta..sub.3
agonists have been described in several patents and published
applications: WO 98/32753, WO 97/46556, WO 97/37646, WO 97/15549,
WO 97/25311, WO 96/16938, WO 95/29159, European Patents 659737,
801060, 714883, 764640, 827746, and U.S. Pat. Nos. 5,561,142,
5,705,515, 5,436,257, and 5,578,620. These compounds were evaluated
in Chinese hamster ovary (CHO) cells test procedures, expressing
cloned human .beta..sub.3 receptors, which predict the effects that
can be expected in humans (Granneman et al., Mol Pharmacol., 1992,
42, 964; Emorine et al., Science, 1989, 245, 1118; Liggett Mol.
Pharmacol., 1992, 42, 634).
[0007] .beta..sub.3-Adrenergic agonists also are useful in
controlling the frequent urge of urination. It has been known that
relaxation of the bladder detrusor is under beta adrenergic control
(Li J H, Yasay G D and Kau S T Pharmacology 1992; 44: 13-18).
Beta-adrenoceptor subtypes are in the detrusor of guinea-pig
urinary bladder. Recently, a number of laboratories have provided
experimental evidence of .beta..sub.3 adrenergic receptors in a
number of animal species including human (Yamazaki Y, Takeda H,
Akahane M, Igawa Y, et al. Br. J. Pharmacol. 1998; 124: 593-599),
and that activation of the .beta..sub.3 receptor subtype by
norepinephrine is responsible for relaxation of the urinary
bladder.
[0008] Urge urinary incontinence is characterized by abnormal
spontaneous bladder contractions that can be unrelated to bladder
urine volume. Urge urinary incontinence is often referred to
hyperactive or unstable bladder. Several etiologies exist and fall
into two major categories, myogenic and neurogenic. The myogenic
bladder is usually associated with detrusor hypertrophy secondary
to bladder outlet obstruction, or with chronic urinary tract
infection. Neurogenic bladders are associated with an uninhibited
micturition reflex. An upper motor neuron disease is usually the
underlying cause. In either case, the disease is characterized my
abnormal spontaneous contractions that result in an abnormal sense
of urinary urgency and involuntary urine loss. At present, the most
common therapy for hyperactive bladder includes the use of
antimuscarinic agents to block the action of the excitatory
neurotransmitter acetylcholine. While effective in neurogenic
bladders, their utility in myogenic bladders is questionable. In
addition, due to severe dry mouth side-effects associated with
antimuscarinic therapy, the patient compliance with these agents is
only approximately 30%.
[0009] In the bladder, .beta..sub.3 adrenergic receptor agonists
activate adenylyl cyclase and generate cAMP through the G-protein
coupled .beta..sub.3 receptor. The resulting phosphorylation of
phospholamban/calcium ATPase enhances uptake of calcium into the
sarcoplasmic reticulum. The decrease in intracellular calcium
inhibits bladder smooth muscle contractility.
[0010] It is suggested therefore, that activation of the
.beta..sub.3 adrenergic receptor in the urinary bladder will
inhibit abnormal spontaneous bladder contractions and be useful for
the treatment of bladder hyperactivity. Note, that unlike the
antimuscarinics, .beta..sub.3 adrenergic receptor agonists would be
expected to be active against both neurogenic and myogenic
etiologies.
[0011] Despite all these recent developments there is still no
single therapy available for the treatment of type II diabetes
(NIDDM), obesity, atherosclerosis, gastrointestinal disorders,
neurogenetic inflammation, frequent urination and related diseases.
A potent and selective .beta..sub.3 adrenergic receptor agonist is
therefore highly desirable for the potential treatment of such
disease states.
DESCRIPTION OF THE INVENTION
[0012] This invention provides compounds of Formula I having the
structure 2
[0013] wherein:
[0014] W is (CH.sub.2).sub.m;
[0015] X is (CH.sub.2).sub.n;
[0016] Y is OCH.sub.2, SCH.sub.2, or a bond;
[0017] R.sub.1 is phenyl substituted with R.sub.5 and R.sub.6, or
Het substituted with R.sub.5 and R.sub.6;
[0018] R.sub.2 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon
atoms, alkenyl of 2-7 carbon atoms, or alkynyl of 2-7 carbon
atoms;
[0019] R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms,
hydroxy, aryl substituted with R.sub.5 and R.sub.6, Het substituted
with R.sub.5 and R.sub.6, aryloxy, --NHCOR.sub.7,
--NR.sub.8R.sub.8, --CR.sub.3R.sub.5R.sub.6, arylamino, Het-amino,
arylalkylamino having 1-6 carbon atoms in the alkyl chain,
Het-alkylamino having 1-6 carbon atoms in the alkyl chain,
alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl of 2-7
carbon atoms, alkylcarbonylalkyl of 3-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminosulfonylalkyl having 1-6 carbon atoms
in the alkyl chain, phosphonylalkyl of 1-6 carbon atoms, or
phosphorylalkyl of 1-6 carbon atoms;
[0020] R.sub.3, R.sub.5, and R.sub.6, are each, independently,
hydrogen, trifluoromethyl, alkyl of 1-6 carbon atoms, alkenyl of
2-7 carbon atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8
carbon atoms, aryl, Het, arylalkyl having 1-6 carbon atoms in the
alkyl chain, Het-alkyl having 1-6 carbon atoms in the alkyl chain,
halogen, cyano, nitro, hydroxy, alkoxy of 1-6 carbon atoms,
aryloxy, arylalkyloxy having 1-6 carbon atoms in the alkyl chain,
alkylthio 1-6 carbon atoms, arylthio, arylamino, Het-amino,
arylalkylamino of 1-6 carbons in the alkyl chain, Het-alkylamino
having 1-6 carbon atoms in the alkyl chain, hydroxyamino,
--NHCOR.sub.7, --NHSO.sub.2R.sub.7, --NHP(O)(R.sub.7).sub.2,
--COR.sub.8, --SO.sub.2R.sub.8, --NR.sub.8R.sub.8, carboxy,
alkylcarbonyl of 2-7 carbon atoms, formylalkyl of 2-7 carbon atoms,
phosphoryl, alkoxycarbonylalkyl of 3-13 carbon atoms, carboxyalkyl
of 2-7 carbon atoms, alkylcarbonylalkyl of 2-13 carbon atoms,
arylcarbonylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-carbonylalkyl having 1-6 carbon atoms in the alkyl chain,
aminocarbonylalkyl of 2-7 carbon atoms, alkylaminocarbonylalkyl of
3-13 carbon atoms, arylaminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, Het-aminocarbonylalkyl having 1-6 carbon atoms
in the alkyl chain, aminosulfonylalkyl of 1-6 carbon atoms,
alkylsulfonylalkyl of 2-12 carbon atoms, arylsulfonylalkyl having
1-6 carbon atoms in the alkyl chain, alkylaminosulfonylalkyl of
2-12 carbon atoms, arylaminosulfonylalkyl of 1-6 carbon atoms,
Het-aminosulfonylalkyl of 1-6 carbon atoms, phosphonylalkyl of 1-6
carbon atoms, or phosphorylalkyl of 1-6 carbon atoms; or R.sub.5
and R.sub.6 may be alkylene groups that are taken together to form
a 3-8 membered cycloalkyl ring when R.sub.5 and R.sub.6 are
attached to a common carbon atom;
[0021] R.sub.7 is hydrogen, trifluoromethyl, alkyl of 1-6 carbon
atoms, cycloalkyl of 3-8 carbon atoms, alkenyl of 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, aryl, alkoxy of 1-6 carbon atoms,
--NR.sub.8R.sub.9, or --NR.sub.9(CH.sub.2).sub.p--R.sub.8
[0022] R.sub.8 is hydrogen, alkoxy of 1-6 carbon atoms, alkyl of
1-6 carbon atoms, hydroxy, aryl substituted with R.sub.5 and
R.sub.6, arylalkoxy having 1-6 carbon atoms in the alkyl chain,
--CR.sub.3R.sub.5R.sub.6, --(CH.sub.2).sub.p--COR.sub.9, or
--(CH.sub.2).sub.p--R.sub.9;
[0023] R.sub.9 is hydrogen, hydroxy, alkyl of 1-6 carbon atoms,
cycloalkyl of 3-8 carbon atoms, alkoxy of 1-6 carbon atoms, aryl
substituted with R.sub.5 and R.sub.6, Het substituted with R.sub.5
and R.sub.6, arylalkoxy having 1-6 carbon atoms in the alkyl chain,
or --NR.sub.10R.sub.10;
[0024] R.sub.10 is hydrogen, alkyl of 1-6 carbon atoms,
alkoxycarbonyl of 2-7 carbon atoms, hydroxy, aryl substituted with
R.sub.5 and R.sub.6, or Het substituted with R.sub.5 and
R.sub.6;
[0025] Het is a monocyclic or bicyclic heterocycle of 5-10 ring
atoms, having 1-4 heteroatoms selected from oxygen, nitrogen, and
sulfur; wherein the heterocycle may be saturated, unsaturated, or
partially unsaturated; and may be optionally fused to a phenyl
ring;
[0026] m is 1-3;
[0027] n is 1-3;
[0028] p is 0-6;
[0029] or a pharmaceutically acceptable salt thereof, which are
selective agonists at human .beta..sub.3 adrenergic receptors and
are useful as antidiabetic, antihyperglycemic, and antiobesity
agents.
[0030] Pharmaceutically acceptable salts can be formed from organic
and inorganic acids, for example, acetic, propionic, lactic,
citric, tartaric, succinic, fumaric, maleic, malonic, mandelic,
malic, phthalic, hydrochloric, hydrobromic, phosphoric, nitric,
sulfuric, methanesulfonic, napthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable
acids when a compound of this invention contains a basic moiety.
Salts may also be formed from organic and inorganic bases, such as
alkali metal salts (for example, sodium, lithium, or potassium)
alkaline earth metal salts, ammonium salts, alkylammonium salts
containing 1-6 carbon atoms or dialkylammonium salts containing 1-6
carbon atoms in each alkyl group, and trialkylammonium salts
containing 1-6 carbon atoms in each alkyl group, when a compound of
this invention contains an acidic moiety.
[0031] Alkyl includes both straight chain as well as branched
moieties. By definition alkyl also includes alkyl moieties which
are optionally mono- or poly substituted with groups such as
halogen, hydroxy, cyano, alkoxy, aryloxy, arylalkyl, alkylthio,
arylthio, amino, alkylamino, and dialkylamino. Halogen means
bromine, chlorine, fluorine, and iodine. Where a substituent
contains one or more moieties which have the same designation
(i.e., --NR.sub.8R.sub.8), each of the moieties can be the same or
different.
[0032] Preferred aryl moieties include phenyl or naphthyl.
Preferred Het moieties include: (a) 6-membered saturated, partially
unsaturated, or unsaturated heterocycles containing 1-2 nitrogens,
optionally fused to a phenyl ring; (b) 5-membered saturated,
partially saturated, or unsaturated heterocycles containing 1-3
nitrogen, oxygen, or sulfur atoms, optionally fused to a phenyl
ring; (c) saturated, partially unsaturated, or unsaturated bicyclic
heterocycles containing 1-4 nitrogen, oxygen, or sulfur atoms; (d)
carbazole, dibenzofuran, and dibenzothiophene. In the Het of
categories (a), (b), and (c), ring carbon atoms may be carbonyl
moieties, where the ring does not contain a double bond in that
position (for example, thiazolidine-2,4-dione).
[0033] More preferred Het rings include pyridine, pyrimidine,
furan, imidazolyl, thiazole, oxazole, isoxazole, pyrazole,
triazole, tetrazole, carbazole, pyrrole, thiophene, imidazole,
imidazol-2-one, imidazole-2-thione, imidazolidine-2,4-dione,
pyrazoline, triazole, tetrazole, oxazolone, oxadiazole,
imidazolone, thiazole, thiazolone, thiadiazole, thiadiazolone,
thiazoladine-2,4-dione, pyridine, pyrimidine, piperazine, pyrazine,
pyrrolidine, piperidine, morpholine, benzofuran, dibenzofuran,
dibenzothiophene, isobenzofuran, indole, isoindole, benzothiophene,
1,3,-dihydrobenzoimidazol-2-one, benzo[1,2,5]thiadoazole,
2-oxo-2,3-dihydro-1H-benzoimidazole, quinoline, and isoquinoline.
Particularly preferred Het include pyrrolidine, piperazine,
piperidine, thiazole, imidazolidine-2,4-dione, carbazole, and
2-oxo-2,3-dihydro-1H-be- nzoimidazole. It is understood that Het do
not contain heteroatoms in arrangements which would make them
inherently unstable. For example, the term Het does not include
ring systems containing O--O bonds in the ring backbone.
[0034] The compounds of the present invention contain at least one
asymmetric center. Additional asymmetric centers may exist on the
molecule depending upon the structure of the substituents on the
molecule. The compounds may be prepared as a racemic mixture and
can be used as such, or may be resolved into the . In addition to
covering the racemic compounds, this invention also covers all
individual isomers, enantiomers, diasteromers or mixtures thereof,
regardless of whether the structural representations of the
compounds indicate such stereochemistry.
[0035] Preferred compounds of Formula I are those in which
[0036] R.sub.2 is hydrogen;
[0037] R.sub.4 is alkyl of 1-6 carbon atoms, alkenyl of 2-7 carbon
atoms, alkynyl of 2-7 carbon atoms, cycloalkyl of 3-8 carbon atoms,
aryl substituted with R.sub.4 and R.sub.5, Het substituted with
R.sub.5 and R.sub.6, --NR.sub.8R.sub.8, or
--CR.sub.3R.sub.5R.sub.6;
[0038] R.sub.3, R.sub.5, and R.sub.6 are each, independently,
hydrogen, alkyl of 1-6 carbon atoms, alkenyl fo 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, halogen, hydroxy, alkoxy of 1-6 carbon
atoms, arylalkoxy having 1-6 carbon atoms in the alkyl chain,
hydroxy, arylalkyl having 1-6 carbon atoms in the alkyl chain,
Het-alkyl having 1-6 carbon atoms in the alkyl chain,
--NHCOR.sub.7, --NHSO.sub.2R.sub.7, --NR.sub.8R.sub.8, --COR.sub.8,
formylalkyl of 2-7 carbon atoms, or alkoxycarbonylalkyl of 3-13
carbon atoms, or R.sub.5 and R.sub.6 may be alkylene groups that
are taken together to form a 3-8 membered cycloalkyl ring when
R.sub.5 and R.sub.6 are attached to a common carbon atom;
[0039] Het is (a) a 6-membered saturated, partially unsaturated, or
unsaturated heterocycle containing 1-2 nitrogens, optionally fused
to a phenyl ring; (b) a 5-membered saturated, partially saturated,
or unsaturated heterocycle containing 1-3 nitrogen, oxygen, or
sulfur atoms, optionally fused to a phenyl ring; (c) a saturated,
partially unsaturated, or unsaturated bicyclic heterocycle
containing 1-4 nitrogen, oxygen, or sulfur atoms; (d) carbazole,
dibenzofuran, and dibenzothiophene; wherein one or more of the ring
carbon atoms of Het as described in (a), (b), or (c) may be a
carbonyl moiety, where the ring does not contain a double bond in
the position corresponding to that carbon atom;
[0040] or a pharmaceutically acceptable salt thereof.
[0041] More preferred compounds of Formula I are those in which
[0042] Y is OCH.sub.2 or a bond;
[0043] R.sub.2 is hydrogen;
[0044] R.sub.4 is aryl substituted with R.sub.4 and R.sub.5, Het
substituted with R.sub.5 and R.sub.6, --NR.sub.8R.sub.8, or
--CR.sub.3R.sub.5R.sub.6;
[0045] R.sub.3, R.sub.5, and R.sub.6 are each, independently,
hydrogen, alkyl of 1-6 carbon atoms, alkenyl fo 2-7 carbon atoms,
alkynyl of 2-7 carbon atoms, halogen, hydroxy, alkoxy of 1-6 carbon
atoms, arylalkoxy having 1-6 carbon atoms in the alkyl chain,
hydroxy, --NHSO.sub.2R.sub.7, --NR.sub.8R.sub.8, --COR.sub.8,
formylalkyl of 2-7 carbon atoms, or alkoxycarbonylalkyl of 3-13
carbon atoms, or R.sub.5 and R.sub.6 may be alkylene groups that
are taken together to form a 3-8 membered cycloalkyl ring when
R.sub.5 and R.sub.6 are attached to a common carbon atom;
[0046] Het is pyridine, pyrimidine, furan, imidazolyl, thiazole,
oxazole, isoxazole, pyrazole, triazole, tetrazole, carbazole,
pyrrole, thiophene, imidazole, imidazol-2-one, imidazole-2-thione,
imidazolidine-2,4-dione, pyrazoline, triazole, tetrazole,
oxazolone, oxadiazole, imidazolone, thiazole, thiazolone,
thiadiazole, thiadiazolone, thiazoladine-2,4-dione, pyridine,
pyrimidine, piperazine, pyrazine, pyrrolidine, piperidine,
morpholine, benzofuran, dibenzofuran, dibenzothiophene,
isobenzofuran, indole, isoindole, benzothiophene,
1,3,-dihydrobenzoimidazol-2-one, benzo[1,2,5]thiadoazole,
2-oxo-2,3-dihydro-1H-benzoimidazole, quinoline, or
isoquinoline;
[0047] or a pharmaceutically acceptable salt thereof.
[0048] Specifically preferred compounds of this invention are:
[0049] a)
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-{4-[2-hydroxy-3-(2-oxo-2,3-d-
ihydro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfo-
namide;
[0050] b)
N-Benzyl-N-butyl-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-be-
nzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
[0051] c)
N-Benzyl-N-butyl-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonyla-
mino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
[0052] d)
N-Benzyl-4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-
-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
[0053] e)
N-Benzyl-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phe-
nyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
[0054] f)
N-Benzyl-4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-
-piperidin-1-yl}-benzenesulfonamide;
[0055] g)
N-(3,4-Dimethoxy-phenyl)-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihyd-
ro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonami-
de;
[0056] h)
N-(3,4-Dimethoxy-phenyl)-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanes-
ulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
[0057] i)
4-{4-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperi-
din-1-;
[0058] j) yl}-N-(3,4-dimethoxy-phenyl)-benzenesulfonamide;
[0059] k)
4-{4-[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxy-propylamino]-piperi-
din-1-yl}-N-(3,4-dimethoxy-phenyl)-benzenesulfonamide;
[0060] l)
N-(3,4-Dimethoxy-phenyl)-4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-pheno-
xy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
[0061] m)
N-Butyl-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidaz-
ol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide;
[0062] n)
N-Butyl-4-{4-[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamino-
]piperidin-1-yl}-benzenesulfonamide;
[0063] o)
N-Butyl-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-
phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
[0064] p)
1-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)et-
hylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid isopropyl ester;
[0065] q)
1-(4-{4-[2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy-
)propylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid isopropyl ester;
[0066] r)
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4--
yloxy)propylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxyl-
ic acid methylamide;
[0067] s)
1-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)et-
hylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid;
[0068] t)
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-
phenyl)-ethylamino]piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid benzyl ester;
[0069] u)
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-
phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid;
[0070] v)
(2R)-1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-
-phenyl)ethylamino)-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxy-
lic acid benzyl ester;
[0071] w)
(2S)-1-(4-{4-[2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino--
phenyl)ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxyl-
ic acid benzyl ester;
[0072] x)
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-
-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid ethyl ester-1-yl}-phenyl)-amino]-acetic acid;
[0073] y)
N-(2-Hydroxyethyl)-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesu-
lfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
[0074] z)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-pheny-
l)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-methyl-amino]-acetic
acid ethyl ester;
[0075] aa)
N-Cyclopropylmethyl-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methane-
sulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide;
[0076] bb)
4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl-
)-ethylamino]-piperidin-1-yl}-N-isobutyl-benzenesulfonamide;
[0077] cc)
[Cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methane-
sulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]--
acetic acid ethyl ester;
[0078] dd)
4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl-
)-ethylamino]-piperidin-1-yl}-N-isopropyl-benzenesulfonamide;
[0079] ee)
1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phe-
nyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-(2R)-2-carbo-
xylic acid ethyl ester;
[0080] ff)
[Cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methane-
sulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]--
acetic acid;
[0081] gg)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phen-
yl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-isobutyl-amino]-acetic
acid ethyl ester;
[0082] hh)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phen-
yl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-methyl-amino]-acetic
acid;
[0083] ii)
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phen-
yl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-isobutyl-amino]-acetic
acid;
[0084] jj)
1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phe-
nyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-(2R)-2-carbo-
xylic acid;
[0085] kk)
ethyl(2S)-1-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulf-
onyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-2-pyrrolidin-
ecarboxylate;
[0086] ll)
ethyl(2S)-2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsul-
fonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}-4-met-
hylpentanoate;
[0087] mm)
ethyl(2S)-2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsul-
fonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}-3-met-
hylbutanoate;
[0088] nn)
(2S)-1-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)-
amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-2-pyrrolidinecarb-
oxylic acid;
[0089] oo) ethyl
1-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-nyl}phenyl)sulf-
onyl]amino}cyclopentanecarboxylate;
[0090] pp)
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-({1-[4-(1-pyrrolidinylsulfonyl-
)phenyl]-4-lidinylsulfonyl)phenyl]-4-piperidinyl}amino)ethyl]phenyl}methan-
esulfonamide;
[0091] qq)
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-({1-[4-(1-piperidinylsulfonyl)-
phenyl]-4-idinylsulfonyl)phenyl]-4-piperidinyl}amino)ethyl]phenyl}methanes-
ulfonamide;
[0092] rr) Ethyl
1-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-inyl}phenyl)sul-
fonyl]amino}cyclohexanecarboxylate;
[0093] ss) Ethyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-idinyl}phenyl)sul-
fonyl](isopropyl)amino]acetate;
[0094] tt)
N-[2-Hydroxy-5-(1-hydroxy-2-{1-[4-(toluene-4-sulfonyl)-phenyl]--
piperidin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide;
[0095] uu)
4-((2S)-2-Hydroxy-3-{1-[4-(toluene-4-sulfonyl)-phenyl]-piperidi-
n-4-ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one;
[0096] vv)
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methyl-
sulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-4-hexyn-
oicacid tert-butyl ester;
[0097] ww)
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methyl-
sulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-4-hexyn-
oic acid;
[0098] xx)
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-
-yloxy)propylamino]-piperidin-1-yl}-benzenesulfonyl)-imidazolidine-2,4-dio-
ne;
[0099] yy)
N-[5-((1R)-2-{1-[4-(2,4-Dioxo-imidazolidine-1-sulfonyl)-phenyl]-
piperidin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide-
;
[0100] zz)
1-(4-{4-[((2S)-2-Hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-eth-
ylamino]-piperidin-1-yl)-benzenesulfonyl)-imidazolidine-2,4-dione;
[0101] aaa) tert-Butyl
2-{[(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methyls-
ulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acet-
ate;
[0102] bbb)
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)ami-
no]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetic
acid;
[0103] ccc) tert-Butyl
2-{[2-(tert-butoxy)-2-oxoethyl][(4-{4-[((2R)-2-hydr-
oxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidiny-
l}phenyl)sulfonyl]amino}acetate;
[0104] ddd)
2-{(Carboxymethyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(met-
hylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}-
acetic acid;
[0105] eee) Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfon-
yl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate;
[0106] fff) Methyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfo-
nyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate;
[0107] ggg) Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfon-
yl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]amino}acetylcar-
bamate;
[0108] hhh) tert-Butyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3[(methylsulf-
onyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl](methoxycarbo-
nyl)amino]acetate;
[0109] iii)
[[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino-
]phenyl)ethyl)amino]piperidin-1-yl}phenyl)sulfonyl](methoxycarbonyl)amino]-
acetic acid;
[0110] jjj) Ethyl
{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydrox-
y-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfon-
yl]amino}acetate;
[0111] kkk)
1-[4-({[(Butylamino)carbonyl]amino}sulfonyl)phenyl]-4-[((2R)-2-
-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidi-
ne;
[0112] lll)
2-{(2,5-Difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3--
[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]a-
mino}acetic acid;
[0113] mmm) Ethyl
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfon-
yl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}-
acetate;
[0114] nnn)
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)ami-
no]-phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}aceti-
c acid;
[0115] ooo)
N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[(1-{4-[(4-methylpiperazin-1--
yl)sulfonyl]phenyl}piperidin-4-yl)amino]ethyl}phenyl)methanesulfonamide;
[0116] ppp) tert-Butyl
{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-h-
ydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)s-
ulfonyl]amino}acetate;
[0117] or a pharmaceutically acceptable salt thereof; and
[0118]
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]-p-
henyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}acetic
acid, sodium salt.
[0119] The compounds of this invention were be prepared according
to the following schemes from commercially available starting
materials or starting materials which can be prepared using
literature procedures. These schemes show the preparation of
representative compounds of this invention. 3 4 5 6 7 8 9
[0120] In general, as shown in Scheme 1, compounds of the present
invention are prepared by reductive amination of
N-(4-sulfonylaryl)-subst- ituted oxo-cyclylamines with the
appropriate aryl-substituted ethanolamines. Various oxo-cycylamine
derivatives can be prepared according to one of the synthetic
Schemes 2 to 7.
[0121] Many of the aryloxypropanolamines and arylethanolamines used
in Scheme 1 are commerically available or readily prepared by known
methods [e.g., 1. A. Guy, Synthesis, 1992, 821; 2. A. A. Asselin,
J. Med. Chem., 1986, 1009; 3. M. S. Berridge et al., Nucl. Med.
Biol., 19, 1992, 563; 4. C. D. Jesudason, et al., EP0764640; 5.
EP0659737.]. In one method (Scheme 8), equimolar amounts of a
substituted phenol and (2S) or (2R)-glycidyl
3-nitrobenzenesulfonate are dissolved in an organic solvent such as
acetone or dimethylformamide and treated with a base such as sodium
hydride or potassium carbonate for 0.5 to 24 hours at temperatures
of 20 to 100.degree. C. to provide the corresponding
aryloxyoxiranes. The aryloxyoxiranes are converted to the
ethanolamines by regioselective ring opening of the oxirane with
lithium azide in a solvent such as hexamethylphosphoramide,
followed by reduction with triphenylphosphine or hydrogenation with
10% Pd/C as catalyst. Alternatively, the aryloxyoxiranes can be
converted to the ethanolamines by regioselective ring opening of
the oxirane with dibenzylamine, followed by hydrogenation with 10%
Pd/C as catalyst. 10
[0122] The arylethanolamines used in Scheme 1 can be prepared
according to the methods shown in Scheme 9. Arylmethylketones are
converted to the corresponding .alpha.-haloketones using known
methods [J. March, Advanced Organic Chemistry, 3rd Ed., John Wiley
and Sons, New York: 1985, p529 and references cited therein]. The
haloketones are reduced to the corresponding alcohol which can be
protected as the triethylsilyl ether, or converted directly to the
ethanolamine by treatment with ammonia or sodium azide followed by
reduction. Treatment of the halo silyl ether with benzylamine
followed by desilylation and hydrogenation also gives the
corresponding arylethanolamine. 11
[0123] The compounds of this invention are useful in treating
metabolic disorders related to insulin resistance or hyperglycemia,
typically associated with obesity or glucose intolerance. The
compounds of this invention are therefore, particularly useful in
the treatment or inhibition of type II diabetes. The compounds of
this invention are also useful in modulating glucose levels in
disorders such as type I diabetes.
[0124] The ability of compounds of this invention to treat or
inhibit disorders related to insulin resistance or hyperglycemia
was established with representative compounds of this invention in
the following standard pharmacological test procedures, which
measured the binding selectivity to the .beta..sub.1, .beta..sub.2
and .beta..sub.3 adrenergic receptors. Binding to the receptors was
measured in Chinese Hamster ovary (CHO) cells that were transfected
with adrenergic receptors. The following briefly summarizes the
procedures used and results obtained.
[0125] Transfection of CHO cells with .beta..sub.1 and .beta..sub.2
adrenergic receptors: CHO cells were transfected with human
.beta..sub.1- or .beta..sub.2-adrenergic receptors as described in
Tate, K. M, Eur. J. Biochem., 196:357-361 (1991).
[0126] Cloning of Human .beta..sub.3-AR Genomic DNA: cDNA was
constructed by ligating four polymerase chain reaction (PCR)
products using the following primers: an ATG-Narl fragment, sense
primer 5'-CTTCCCTACCGCCCCACGCGCGATC3' and anti-sense primer
5'CTGGCGCCCAACGGCCAGTGGCCAGTC3'; a Narl-Accl fragment,
5'TTGGCGCTGATGGCCACTGGCCGTTTG3' as sense and
5'GCGCGTAGACGAAGAGCATCACGAG3- ' as anti-sense primer; an Accli-Styl
fragment, sense primer 5'CTCGTGATGCTCTTCGTCTCACGCGC3' and
anti-sense primer 5'GTGAAGGTGCCCATGATGAGACCCAAGG3' and a Styl-TAG
fragment, with sense primer 5'CCCTGTGCACCTTGGGTCTCATCATGG3' and
anti-sense primer 5'CCTCTGCCCCGGTTACCTACCC3'. The corresponding
primer sequences are described in Mantzoros, C. S., et.al.,
Diabetes 45: 909-914 (1996). The four fragments are ligated into a
pUC 18 plasmid (Gibco-BRL) and sequenced. Full length .beta..sub.3
AR clones (402 amino acids) containing the last 6 amino acids of
h.beta..sub.3.sub..sub.--AR are prepared with the
.beta..sub.3-.beta.ARpcDNA3 from ATTC.
[0127] Binding Procedure: Clones expressing receptor levels of 70
to 110 fmoles/mg protein were used in the test procedures. CHO
cells were grown in 24-well tissue culture plates in Dulbecco's
Modified Eagle Media with 10% fetal bovine serum, MEM non-essential
amino acids, Penicillin-Streptompycin and Geneticin. On the day of
test procedure, growth medium was replaced with preincubation media
(Dulbecco's Modified Eagle Media and incubated for 30 minutes at
37.degree. C. Preincubation medium was replaced with 0.2 ml
treatment medium containing DMEM media containing 250 .mu.M IBMX
(isobutyl-1-methylxantine) plus 1 mM ascorbic acid with test
compound dissolved in DMSO. Test compounds were tested over a
concentration range of 10.sup.-9 M to 10.sup.-5 M for .beta..sub.3
cells and 10.sup.-8 to 10.sup.-4 M for .beta..sub.1 and
.beta..sub.2 transfected cells. Isoproterenol (10.sup.-5 M) was
used as an internal standard for comparison of activity. Cells were
incubated at 37.degree. C. on a rocker for 30 min with the
.beta..sub.3 cells and 15 min for .beta..sub.1 and .beta..sub.2
cells. Incubation was stopped with the addition of 0.2N HCl and
neutralized with 2.5N NaOH. The plates, containing the cells and
neutralized media, were stored at -20 degrees celsius until ready
to test for cAMP using the SPA test kit (Amersham).
[0128] Data Analysis and Results: Data collected from the SPA test
procedure were analyzed as per cent of the maximal isoproterenol
response at 10.sup.-5 M. Activity curves were plotted using the SAS
statistical and graphics software. EC.sub.50 values were generated
for each compound and the maximal response (IA) developed for each
compound is compared to the maximal response of isoproternol at
10.sup.-5 M from the following formula:
IA=% activity compound/% activity isoproterenol
[0129] Table I shows the EC.sub.50 and IA values for the
representative compounds of this invention that were evaluated in
this standard pharmacological test procedure that measured binding
selectivity at that .beta.-adrenergic receptors.
1 TABLE I beta-3 beta-2 beta-1 Example EC.sub.50 .mu.M (IA)
EC.sub.50 .mu.M (IA) EC.sub.50 .mu.M (IA) 1 0.017 (0.92) (0) (0.09)
2 0.094 (1.1) (0.03) (0.16) 3 0.015 (1.1) 0.31 (0.59) 2.1 (0.66) 4
0.021 (0.78) (0) (0.17) 5 0.016 (0.98) (0.07) 2.2 (0.59) 6 0.2
(0.76) 7 0.02 (0.8) (0.01) 0.6 (0.15) 8 0.016 (0.91) 0.61 (0.28)
3.6 (0.41) 10 0.1 (0.45) 11 0.33 (0.83) 12 0.01 (1) 13 0.05 (0.7)
14 0.001 (1.3) 0.17 (0.53) 0.64 (1) 15 0.001 (1) 0.16 (0.37) 13
(0.23) 16 0.003 (0.86) 17 0.028 (0.81) 18 0.041 (0.99) 1 (0.55)
(0.29) 19 0.007 (1) (0.2) 0.79 (0.54) 20 0.01 (1) 10 (0.3) 10 (0.4)
21 0.001 (1) 0.64 (0.82) 0.06 (0.88) 22 0.002 (1) 0.04 (0.63) 0.2
(1.08) 23 0.016 (1) 1.67 (0.89) 1.32 (0.68) 24 0.033 (0.88) 1
(0.68) 1 (0.35) 25 0.052 (1) 1.43 (0.37) 1 (0.63) 26 0.023 (0.98)
0.27 (0.29) 0.24 (0.41) 27 0.002 (1) 0.54 (0.29) 0.42 (0.22) 28
0.002 (0.94) 6.6 (0.85) (0.24) 29 0.007 (1.3) 2.9 (0.48) 2.0 (0.57)
30 0.004 (1.2) 3.6 (0.36) 9.8 (1.1) 31 0.007 (1.2) 12 (0.33) 20
(0.96) 32 0.004 (1) 10 (0.57) 6.7 (0.48) 33 0.018 (1) (0.15) 25
(0.66) 34 0.006 (1.1) (0.14) 10 (0.49) 35 0.011 (1.1) (0.04) 49
(0.66) 36 0.009 (1) 0.72 (0.19) 4.8 (0.85) 37 0.016 (0.89) 0.9
(0.42) 5.6 (0.43) 38 0.032 (1.1) 0.38 (0.32) 1.1 (0.5) 39 0.03 (1)
(0.23) 10 (0.42) 40 0.004 (1.2) 0.04 (0.31) 1.9 (0.45) 41 0.002 (1)
2 (0.24) 0.8 (0.58) 42 0.001 (1) 0.37 (0.35) 1.32 (0.69) 43 0.001
(1) 0.09 (0.68) 1.28 (0.58) 44 0.003 (0.95) 2 (0.43) 12 (0.71) 45
0.001 (1) 0.7 (0.63) 0.02 (0.74) 46 0.009 (1.1) 47 0.006 (0.93) 3.2
(0.46) 1 (0.47) 48 0.59 (1) 10 (0.54) 10 (0.26) 49 0.009 (0.96) 50
0.01 (1) 7 (0.35) 2.6 (0.72) 52 0.006 (1) 0.48 (0.65) 0.96 (0.48)
53 0.034 (1.2) (0.23) (0.24) 54 0.014 (1.2) 12 (0.42) 2.3 (0.33) 55
0.41 (0.94) 56 0.014 (1) 1.6 (0.27) 9.5 (0.31) 57 0.006 (0.85)
(0.18) (0.18) 58 0.011 (1) 3.9 (0.31) 3.6 (0.65) 59 0.015 (0.98) 12
(0.2) 7.8 (0.52) 60 0.021 (1.1) 10 (0.21) 10 (0.18) 61 0.001 (1.1)
(0.2) 1.9 (0.3) 62 0.009 (1) 5 (0.31) 5 (0.32) 63 0.005 (0.91)
(0.15) 10 (0.88) 64 0.004 (1.1) 5.9 (0.22) (0.11) 65 0.16 (0.93) 16
(0.67) (0.23) 66 0.025 (0.95) (0.17) 2.7 (0.44) 67 0.005 (0.96)
(0.17) 1 (0.48)
[0130] Based on the results obtained in these standard
pharmacological test procedures, representative compounds of this
invention have been shown to be selective .beta..sub.3 adrenergic
receptor agonists and are therefore useful in treating metabolic
disorders related to insulin resistance or hyperglycemia, typically
associated with obesity or glucose intolerance. More particularly,
the compounds of this invention useful in the treatment or
inhibition of type II diabetes, and in modulating glucose levels in
disorders such as type I diabetes. As used herein, the term
modulating means maintaining glucose levels within clinically
normal ranges.
[0131] As used in accordance with this invention, the term
providing an effective amount means either directly administering
such a compound of this invention, or administering a prodrug,
derivative, or analog which will form an effective amount of the
compound of this invention within the body.
[0132] It is understood that the effective dosage of the active
compounds of this invention may vary depending upon the particular
compound utilized, the mode of administration, the condition, and
severity thereof, of the condition being treated, as well as the
various physical factors related to the individual being treated.
For treating treating metabolic disorders related to insulin
resistance or hyperglycemia generally satisfactory results may be
obtained when the compounds of this invention are administered to
the individual in need at a daily dosage of from about 0.1 mg to
about 1 mg per kilogram of body weight, preferably administered in
divided doses two to six times per day, or in a sustained release
form. For most large mammals, the total daily dosage is from about
3.5 mg to about 140 mg. It is preferred that the administration of
one or more of the compounds herein begin at a low dose and be
increased until the desired effects are achieved.
[0133] Such doses may be administered in any manner useful in
directing the active compounds herein to the recipient's
bloodstream, including orally, via implants, parenterally
(including intravenous, intraperitoneal and subcutaneous
injections), rectally, intranasally, vaginally, and transdermally.
For the purposes of this disclosure, transdermal administrations
are understood to include all administrations across the surface of
the body and the inner linings of bodily passages including
epithelial and mucosal tissues. Such administrations may be carried
out using the present compounds, or pharmaceutically acceptable
salts thereof, in lotions, creams, foams, patches, suspensions,
solutions, and suppositories (rectal and vaginal).
[0134] Oral formulations containing the active compounds of this
invention may comprise any conventionally used oral forms,
including tablets, capsules, buccal forms, troches, lozenges and
oral liquids, suspensions or solutions. Capsules may contain
mixtures of the active compound(s) with inert fillers and/or
diluents such as the pharmaceutically acceptable starches (e.g.
corn, potato or tapioca starch), sugars, artificial sweetening
agents, powdered celluloses, such as crystalline and
microcrystalline celluloses, flours, gelatins, gums, etc. Useful
tablet formulations may be made by conventional compression, wet
granulation or dry granulation methods and utilize pharmaceutically
acceptable diluents, binding agents, lubricants, disintegrants,
suspending or stabilizing agents, including, but not limited to,
magnesium stearate, stearic acid, talc, sodium lauryl sulfate,
microcrystalline cellulose, carboxymethylcellulose calcium,
polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan
gum, sodium citrate, complex silicates, calcium carbonate, glycine,
dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate,
lactose, kaolin, mannitol, sodium chloride, talc, dry starches and
powdered sugar. Oral formulations herein may utilize standard delay
or time release formulations to alter the absorption of the active
compound(s).
[0135] In some cases it may be desirable to administer the
compounds directly to the airways in the form of an aerosol.
[0136] The compounds of this invention may also be administered
parenterally or intraperitoneally. Solutions or suspensions of
these active compounds as a free base or pharmacologically
acceptable salt can be prepared in water suitably mixed with a
surfactant such as hydroxy-propylcellulose. Dispersions can also be
prepared in glycerol, liquid polyethylene glycols and mixtures
thereof in oils. Under ordinary conditions of storage and use,
these preparation contain a preservative to prevent the growth of
microorganisms.
[0137] The pharmaceutical forms suitable for injectable use include
sterile aqueous solutions or dispersions and sterile powders for
the extemporaneous preparation of sterile injectable solutions or
dispersions. In all cases, the form must be sterile and must be
fluid to the extent that easy syringability exists. It must be
stable under the conditions of manufacture and storage and must be
preserved against the contaminating action of microorganisms such
as bacteria and fungi. The carrier can be a solvent or dispersion
medium containing, for example, water, ethanol, polyol (e.g.,
glycerol, propylene glycol and liquid polyethylene glycol),
suitable mixtures thereof, and vegetable oils.
[0138] Suppository formulations may be made from traditional
materials, including cocoa butter, with or without the addition of
waxes to alter the suppository's melting point, and glycerin. Water
soluble suppository bases, such as polyethylene glycols of various
molecular weights, may also be used.
[0139] The compounds of the present invention also possess utility
for increasing lean meat deposition and/or improving lean meat to
fat ratio in edible animals, i.e. ungulate animals and poultry.
[0140] Animal feed compositions effective for increasing lean meat
deposition and for improving lean meat to fat ratio in poultry,
swine, sheep, goats, and cattle are generally prepared by mixing
the compounds of the present invention with a sufficient amount of
animal feed to provide from about 1 to 1000 ppm of the compound in
the feed. Animal feed supplements can be prepared by admixing about
75% to 95% by weight of a compound of the present invention with
about 5% to about 25% by weight of a suitable carrier or diluent.
Carriers suitable for use to make up the feed supplement
compositions include the following: alfalfa meal, soybean meal,
cottonseed oil meal, linseed oil meal, sodium chloride, cornmeal,
cane molasses, urea, bone meal, corncob meal and the like. The
carrier promotes a uniform distribution of the active ingredients
in the finished feed into which the supplement is blended. It thus
performs an important function by ensuring proper distribution of
the active ingredient throughout the feed. The supplement is used
as a top dressing for the feed, it likewise helps to ensure
uniformity of distribution of the active material across the top of
the dressed feed.
[0141] The preferred medicated swine, cattle, sheep and goat feed
generally contain from 0.01 to 400 grams of active ingredient per
ton of feed, the optimum amount for these animals usually being
about 50 to 300 grams per ton of feed. The preferred poultry and
domestic pet feed usually contain about 0.01 to 400 grams and
preferably 10 to 400 grams of active ingredient per ton of
feed.
[0142] For parenteral administration the compounds of the present
invention may be prepared in the form of a paste or a pellet and
administered as an implant, usually under the skin of the head or
ear of the animal in which increase in lean meat deposition and
improvement in lean mean to fat ratio is sought. In general,
parenteral administration involves injection of a sufficient amount
of the compounds of the present invention to provide the animal
with 0.001 to 100 mg/kg/day of body weight of the active
ingredient. The preferred dosage for swine, cattle, sheep and goats
is in the range of from 0.001 to 50 mg/kg/day of body weight of
active ingredient; whereas, the preferred dose level for poultry
and domestic pets is usually in the range of from 0.001 to 35
mg/kg/day of body weight.
[0143] Paste formulations can be prepared by dispersing the active
compounds in a pharmaceutically acceptable oil such as peanut oil,
sesame oil, corn oil or the like. Pellets containing an effective
amount of the compounds of the present invention can be prepared by
admixing the compounds of the present invention with a diluent such
as carbowax, carnuba wax, and the like, and a lubricant, such as
magnesium or calcium stearate, can be added to improve the
pelleting process. It is, of course, recognized that more than one
pellet may be administered to an animal to achieve the desired dose
level which will provide the increase in lean meat deposition and
improvement in lean meat to fat ratio desired. Moreover, it has
been found that implants may also be made periodically during the
animal treatment period in order to maintain the proper drug level
in the animal's body. For the poultry and swine raisers, using the
method of the present invention yields leaner animals.
[0144] Additionally, the compounds of this invention are useful in
increasing the lean mass to fat ratio in domestic pets, for the pet
owner or veterinarian who wishes to increase leanness and trim
unwanted fat from pet animals, the present invention provides the
means by which this can be accomplished.
[0145] The following procedures describe the preparation of
representative aryloxypropanolamines and arylethanolamines used in
the preparation of compounds of this invention.
[0146] (1R)-2-Amino-1-(3-chloro-phenyl)-ethanol:
[0147] Lithium azide (7.5 g, 150 mmol) was added to a solution of
(1R)-1-(3-chlorophenyl)oxirane (15.5 g, 100 mmol) in
hexamethylphosphoramide (70 mL). After being stirred at room
temperature for 16 hours the suspension was poured into ice-water
and the mixture was extracted with diethyl ether. The combined
extracts were dried (MgSO.sub.4) and concentrated. The residue was
dissolved in 550 mL of THF/H.sub.2O (10:1) and triphenylphosphine
(30 g, 114 mmol) was added. After overnight stirring at room
temperature, the solvents were removed and the residue was purified
by column chromatography on silica gel using
triethylamine-methanol-methylene chloride (1:1:8) as the eluent to
give the title compound as a free base. The free base was then
dissolved in diethyl ether and slowly treated with HCl gas. The
precipitate was collected by filtration to yield 15 g (72%) of the
title compound as a white powder; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 2.83 (dd, J=12.8, 9.5 Hz, 1H), 3.06 (dd,
J=12.8, 3.2 Hz, 1H), 4.80-4.90 (m, 1H), 6.22 (d, J=4.0 Hz, 1H),
7.10-7.75 (m, 4H), 8.08 (brs, 2 ); MS (ES) m/z: 171.7, 173.7
(M.sup.++H); HRMS Calcd. for C.sub.8H.sub.10ClNO(M.sup.+):
172.0529. Found: 172.0531.
[0148] (2S)-1-Amino-3-(4-benzyloxy-phenoxy)-propan-2-ol:
[0149] The title compound was prepared from
(2S)-2-(4-benzyloxy-phenoxymet- hyl-oxirane (EP 0 714 883)
according to the procedure described above as a white solid;
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 2.50-2.70 (m, 2H), 3.33
(brs, 2H), 3.60-3.90 (m, 3H), 5.02 (s, 2H), 6.90 (d, J=6.7 Hz, 2H),
6.93 (d, J=6.7 Hz, 2H), 7.25-7.50 (m, 5H); MS (ES) m/z : 274.1
(M.sup.++H); HRMS Calcd. for C.sub.16H.sub.19NO.sub.3(M.sup.+):
273.1365. Found: 273.1347. Anal. Calcd. for
C.sub.16H.sub.19NO.sub.3: C, 70.31; H, 7.01; N, 5.12. Found: C,
70.39; H, 6.80; N, 5.23.
[0150] (2S)-1-Amino-3-(4-hydroxy-phenoxy)-propan-2-ol:
[0151] A mixture of
(2S)-1-amino-3-(4-benzyloxy-phenoxy)-propan-2-ol () (0.9 g, 3.3
mmol) 0.2 mL of acetic acid and 10% Pd/C (0.3 g) in 70 mL of
ethanol was pressurized with 20 psi hydrogen and shaken over 2
hours. The catalyst was then removed by filtering through a short
pad of silica gel and the solvent was removed to give the title
compound as an off-white solid; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 1.86 (s, 1H), 2.66 (dd, J=12.8, 5.3 Hz, 1H), 2.85 (dd,
J=12.8, 3.5 Hz, 1H), 3.79-3.95 (m, 3H), 6.67 (d, J=6.6 Hz, 2H),
6.75 (d, J=6.6 Hz, 2H); MS (ES) m/z: 183.1 (M.sup.++H); HRMS Calcd.
for C.sub.9H.sub.13NO.sub.3(M.sup.++H): 183.0895. Found:
183.0892.
[0152]
N-[2-Benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl]-methanesulfo-
namide:
[0153]
N-[2-Benzyloxy-5-(2-chloro-1-oxo-ethyl)-phenyl]-methanesulfonamide
(EP 0 659 737) (17.0 g, 42.8 mmol) was dissolved in 200 mL of
dimethylformamide and treated with dibenzylamine (22.0 g, 110
mmol). The mixture was stirred at room temperature overnight and
then the solvent was removed. The residue was purified by silica
gel chromatography using 20-50% ethyl acetate/hexanes as elute to
give the title compound as a white solid; .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 2.94 (s, 3H), 3.77 (s, 2H), 3.82 (s, 2H), 5.16
(s, 2H), 6.75 (brs, 1H), 6.96 (d, J=8.7 Hz, 1H), 7.20-7.50 (m,
15H), 7.67 (dd, J=8.7, 2.1 Hz, 1H), 8.10 (d, J=2.1 Hz, 1H); MS (ES)
m/z: 515.2 (M.sup.++H); HRMS Calcd. for
C.sub.30H.sub.30N.sub.2O.sub.4S(M.sup.+): 514.1926. Found:
514.1927.
[0154]
N-[2-Benzyloxy-5-(2-dibenzylamino-1-hydroxy-ethyl)-phenyl]-methanes-
ulfonamide:
[0155] Sodium borohydride (0.37 g, 9.7 mmol) was added in portions
to a stirred solution of
N-[2-benzyloxy-5-(2-dibenzylamino-1-oxo-ethyl)-phenyl-
]-methanesulfonamide (1.0 g, 1.9 mmol) in 20 mL of
methanol/tetrahydrofura- n (5:2) at room temperature and the
resulting solution was stirred for 2 hours. Methylene chloride was
added and the resulting solution was washed with aqueous sodium
bicarbonate, dried over MgSO.sub.4 and the solvent was removed.
Recrystallization from methylene chloride/hexanes gave the title
compound as a crystalline solid; .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 2.58 (d, J=6.7 Hz, 2H), 2.86 (s, 2H), 2.92 (s, 2H), 3.55
(d, J=13.5 Hz, 2H), 3.70 (d, J=13.5 Hz, 2H), 4.11 (s, 1H), 4.64 (t,
J=6.7 Hz, 1H), 5.10 (s, 2H), 6.92 (d, J=8.5 Hz, 1H), 7.00 (dd,
J=8.5, 2.0 Hz, 1H), 7.20-7.50 (m, 16H), 7.89 (brs, 1H); MS (ES)
m/z: 517.1 (M.sup.++H); HRMS Calcd. for
C.sub.30H.sub.32N.sub.2O.sub.4S(M.sup.+): 516.2083. Found:
516.2074.
[0156]
N-[2-Benzyloxy-5-(2-amino-(1R)-1-hydroxy-ethyl)-phenyl]-methanesulf-
onamide:
[0157] A mixture of
N-{2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsilyl)oxy]-e-
thyl)-phenyl}-methanesulfonamide (EP 0 659 737) (4.48 g, 8 mmol)
and sodium azide (0.65 g, 10 mmol) in 100 mL of
hexamethylphosphoramide was stirred at 60.degree. C. overnight.
After cooling to room temperature the mixture was diluted with
diethyl ether, washed with water, dried over Na.sub.2SO.sub.4 and
concentrated under reduced pressure. The residue was dissolved in
200 mL of THF/H.sub.2O (10:1) and triphenylphosphine (2.62 g, 10
mmol) was added. After overnight stirring at room temperature, the
solvents were removed and the residue was partitioned between ethyl
acetate and water. The organic layers were combined and dried over
MgSO.sub.4 and concentrated. The residue was redissolved in 100 mL
of THF and tetrabutylammonium fluoride (10 mL, 1 M solution in THF)
was added. The reaction was stirred for 2 hours then the solvent
was removed in vacuo. The residue was purified by column
chromatography on silica gel using triethylamine-methanol-methylene
chloride (1:1:3) to give the title compound as a white solid; MS
(ES) m/z: 337.4 (M.sup.++H).
[0158]
N-[5-(2-Amino-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide-
:
[0159] To a stirred suspension of
N-[2-benzyloxy-5-(2-dibenzylamino-1-hydr-
oxy-ethyl)-phenyl]-methanesulfonamide (1.03 g, 2 mmol) and 10% Pd/C
(0.4 g) in methanol (100 mL) at room temperature is added anhydrous
HCO.sub.2NH.sub.4 (1.26 g, 20 mmol) under a nitrogen atmosphere.
The resulting mixture is refluxed for 2 hours. After cooling to
room temperature the catalyst is removed by filtration through a
celite pad and washed with methanol. The filtrate is evaporated
under reduced pressure to give the titled compound as a pale
yellowish solid; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 2.62
(dd, J=12.6, 8.7 Hz, 1H), 2.75 (dd, J=12.6, 3.7 Hz, 1H), 2.90 (s,
3H), 4.47 (dd, J=8.7, 3.7 Hz, 1H), 6.84 (d, J=9.1 Hz, 1H), 6.96
(dd, J=9.1, 2.0 Hz, 1H), 7.16 (d, J=2.1 Hz, 1H), 8.44 (s, 1H); MS
(ES) m/z: 246.7 (M.sup.++H); HRMS Calcd. for
C.sub.9H.sub.14N.sub.2O.sub.4S(M.sup.+): 246.0674. Found:
246.0672.
[0160]
N-[5-(2-Amino-(1R)-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfon-
amide:
[0161] Method A: A mixture of
N-{2-benzyloxy-5-(2-iodo-(1R)-1-[(triethylsi-
lyl)oxy]-ethyl)-phenyl}-methanesulfonamide (EP 0 659 737) (8.60 g,
15.3 mmol) and benzylamine (21.4 g, 200 mmol) was heated at
60.degree. C. for 24 hours. The reaction mixture was cooled,
diluted with hexanes (500 mL), and the residue was washed with
diethyl ether. The combined solvents were removed and the residue
was purified by silica gel column eluting with 30 to 100%
Et.sub.2O/hexanes. The fractions with molecular weight of 540 were
concentrated and re-dissolved in 200 mL of THF and TBAF (20 mL, 1.0
M solution in THF) was added. After stirring at room temperature
for 4 hours the reaction mixture was then poured into water and
extracted with CH.sub.2Cl.sub.2. The organic layers were passed
through a short pad of silica gel eluting with 10%
methanol/CH.sub.2Cl.sub.2. The solvents were removed and the
residue were dissolved in methanol (200 mL). 10% Pd/C (0.6 g) and
anhydrous HCO.sub.2NH.sub.4 (6.3 g, 100 mmol) were added. The
resulting mixture was refluxed under a nitrogen atmosphere for 2
hours. After cooling to room temperature the catalyst was removed
by filtration through a celite pad and washed with methanol. The
filtrate is evaporated under reduced pressure to give the title
compound as an off-white solid; .sup.1H NMR (300 MHz, MeOH-d.sub.4)
.delta. 2.95 (s, 3H), 2.99 (dd, J=9.7, 9.2 Hz, 1H), 3.07 (dd,
J=9.7, 3.6 Hz, 1H), 4.75 (dd, J=9.2, 3.6 Hz, 1H), 6.90 (d, J=8.3
Hz, 1H), 7.12 (dd, J=8.3, 2.1 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 8.44
(s, 1H); MS (ES) m/z : 246.7 (M.sup.++H) ); HRMS Calcd. for
C.sub.9H.sub.14N.sub.2O.sub.4S: 246.0674. Found: 246.0672.
[0162] Method B: To a stirred solution of
N-[2-benzyloxy-5-(2-Bromo-1-hydr-
oxy-ethyl)-phenyl]-methanesulfonamide (EP 0 659 737) (15.05 g,
0.376 mol) in DMSO (150 ml) was added sodium iodide (3.76 g, 0.376
mol) and sodium azide (9.48 g, 0.150 mol). The mixture was stirred
for 5 days under Nitrogen atmosphere. The reaction mixture was
poured onto water and extracted three times with ethyl acetate. The
combined organic layers were dried over sodium sulfate and
concentrated. The residue was triturated with water and hexanes.
Recovered yellow solid as of
N-[5-((1R)-2-azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methanesulfonamid-
e (12.85 g, 94%): .sup.1H NMR (300 MHz, CDCl.sub.3): .delta. 2.93
(s, 3H), 3.45 (d, J=9.0 Hz, 2H), 3.46 (m, 1H), 5.11 (s, 2H), 6.80
(s, 1H), 6.99 (d, J=8.4 Hz, 1H), 7.15 (dd, J=6 Hz, 2.1 Hz, 1H),
7.26 (s, 1H), 7.39 (s, 5H), 7.53 (d, J=2.1 Hz, 1H); MS (ES) m/z
361.4 (M.sup.+-H, 70%). A mixture of
N-[5-((1R)-2-Azido-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-methan-
esulfonamide () (12.85 g, 0.037 mol) and 10% Palladium on carbon
(2.75 g) in ethanol (100 ml) was hydrogenated under 45 PSI for two
days. The reaction mixture was filtered through celite and
concentrated. The title compound was recovered as a tan solid (6.08
g, 66%): .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.60 (m, 2H),
2.87 (s, 3H), 4.34 (m, 1H), 6.79 (d, J=9.0 Hz, 1H), 6.89 (d, J=9.0
Hz, 2H).
[0163] The following procedures describe the preparation of
intermediates useful in the preparation of compounds of this
invention.
INTERMEDIATE 1
[0164] N-(3,4-Dimethoxy-phenyl)-4-fluoro-benzenesulfonamide
[0165] 3,4-Dimethoxyaniline (1.01 g, 6.99 mM) was added to a
solution of 4-Fluorobenzenesulfonyl chloride (1.50 g, 7.69 mM) in
anhydrous pyridine (10 ml). The reaction was stirred overnight. The
reaction was quenched with 1N HCl.sub.aq. (20 ml) and washed with
ethyl acetate (3.times.20 ml). The organic extracts were combined,
dried (sodium sulfate), solids filtered off and concentrated. The
desired product was isolated using silica gel flash chromatography
of 1.30 g as a yellow solid. H.sup.1 NMR (CDCl.sub.3) .delta. 3.79
(s, 3H), 3.86 (s, 3H), 6.50 (d, 1H, J=4.71 Hz), 6.68 (d, 1H, J=2.64
Hz), 6.71 (d, 1H, J=2.76 Hz), 7.11 (d, 2H, J=8.67 Hz), 7.75 (m,
2H). MS(ES) m/z 328.9; (M+NH.sub.4.sup.+); HRMS for (MH.sup.+)
C.sub.14H.sub.14SFNO.sub.4: 260.1511.
INTERMEDIATE 2
[0166]
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzenesulfonamide
[0167] N-(3,4-Dimethoxy-phenyl)-4-fluoro-benzenesulfonamide (0.51
g, 1.61 mM) was added to a solution of benzyl bromide (0.57 g, 4.82
mM) and potassium carbonate (0.66 g, 4.82 mM) in anhyrous acetone
(10 ml). The reaction was stirred overnight. The undissolved solids
were removed by filtration and the mother liquor was concentrated.
This gum was triturated with hexanes to afford 0.52 g of the
desired product as an off-white solid. H.sup.1 NMR (CDCl.sub.3)
.delta. 3.66 (s, 3H), 3.81 (s, 3H), 6.42 (m, 2H), 6.66 (d, 1H,
J=8.70 Hz), 7.23 (m, 7H), 7.71 (m, 2H). MS(ES) m/z 401.9;
(MH.sup.+); HRMS for C.sub.21H.sub.20SFNO.sub.4: 401.1094.
INTERMEDIATE 3
[0168]
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec--
8-yl)-benzenesulfonamide
[0169] 1,4-Dioxa-8-azaspiro[4.5]decane (0.14 ml, 0.95 mM) was added
to a solution of
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-fluoro-benzenesulfonamide (0.19
g, 0.47 mM) and potassium carbonate (0.66 g, 4.82 mM) in anhyrous
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (5 ml). The
reaction was stirred at 70.degree. C. for two days. The reaction
was quenched with water (50 ml). The precipitate was washed with
water and dried under reduced pressure to afford 0.15 g of the
desired product as a tan solid. H.sup.1 NMR (CDCl.sub.3) .delta.
1.81 (t, 4H, J=5.67 Hz), 3.50 (t, 4H, J=5.97 Hz), 3.65 (s, 3H),
3.81 (s, 3H), 4.01 (s, 4H), 4.66 (s, 2H), 6.43 (d, 1H, J=2.34 Hz),
6.53 (m, 1H), 6.66 (d, 1H, J=8.58 Hz), 6.90 (d, 1H, J=9.03 Hz),
7.19 (m, 6H), 7.53 (d, 2H, J=9.00 Hz). MS(ES) m/z 525.0;
(MH.sup.+); HRMS for C.sub.28H.sub.32SN.sub.2O.sub.6: 525.2049.
INTERMEDIATE 4
[0170] N-Benzyl-4-fluoro-benzenesulfonamide
[0171] The title compound was prepared according to the procedure
of Intermediate 1 as a yellow solid. H.sup.1 NMR (CDCl.sub.3)
.delta. 4.17 (d, 2H, J=6.06 Hz), 4.81 (t,, 1H, J=5.82 Hz), 7.19 (m,
4H), 7.27 (m, 3H), 7.88 (m, 2H). MS(ES) m/z 265.9; (MH.sup.+); HRMS
for C.sub.13H.sub.12S F NO.sub.2: 266.0625.
INTERMEDIATE 5
[0172]
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenes-
ulfonamide
[0173]
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec--
8-yl)-benzenesulfonamide (0.10 g, 0.19 mM) was stirred in 6M HCl (2
ml) and acetone (5 ml) at 60.degree. C. overnight. The reaction
mixture was basified with 5N NaOHaq. (until pH>7) and washed
with ethyl acetate (3.times.10 ml). The organic extracts were dried
with sodium sulfate, passed through a plug of magnesol,
concentrated and triturated with hexanes to afford 0.65 g of the
desired product as a white solid. H.sup.1 NMR (CDCl.sub.3) .delta.
2.58 (t, 4H, J=6.06 Hz), 3.67 (s, 3H), 3.74 (t, 4H, J=6.12 Hz),
3.81 (s, 3H), 4.71 (s, 2H), 6.48 (m, 3H), 6.67 (d, 1H, J=8.46 Hz),
6.93 (d, 2H, J=9.9 Hz), 7.20 (m, 4H), 7.59 (d, 2H, J=4.71 Hz).
MS(ES) m/z 481.0; (MH.sup.+); HRMS for
C.sub.26H.sub.28SN.sub.2O.sub- .5: 481.1778.
INTERMEDIATE 6
[0174]
N-Benzyl-N-(tert-butylcarbonyl)-4-fluoro-benzenesulfonamide
[0175] t-Boc-Anhydride (0.18 g, 0.83 mM) was added to
N-Benzyl-4-fluorobenzenesulfonamide (0.2 g, 0.75 mM) and
4-dimethylaminopyridine (scoopful) in anhydrous methylene chloride
(5 ml). The reaction was stirred for two hours at room temperature.
The reaction was quenched with 1N HCl (20ml) and washed with
methylene chloride (3.times.10 ml). The organic extracts were
combined, dried with sodium sulfate and passed through a plug of
magnesol and concentrated to afford an oil. The oil was triturated
with hexanes to afford 0.22 g of the desired product as a white
solid. H.sup.1 NMR (CDCl.sub.3) .delta. 1.34 (s, 9H), 5.11 (s, 2H),
7.08 (t, 2H, J=3.42 Hz), 7.34 (m, 5H), 7.66 (m, 2H). MS(ES) m/z
383.1; (M+NH.sub.4+); HRMS for C.sub.26H.sub.28SN.sub.2O.sub.5:
366.1179.
INTERMEDIATE 7
[0176]
N-Benzyl-N-butyl-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)benzenesulfo-
namide
[0177] The title compound was prepared according to the procedure
of Intermediate 3 as a yellow solid. H.sup.1 NMR (CDCl.sub.3)
.delta. 0.74 (t, 3H, J=7.26 Hz), 1.08 (m, 2H), 1.29 (m, 2H), 1.79
(t, 4H, J=5.70 Hz), 3.05 (t, 2H, J=7.74 Hz), 3.50 (t, 4H, J=5.76
Hz), 4.01 (s, 4H), 4.27 (s, 2H), 6.93 (d, 2H, J=5.31 Hz), 7.28 (m,
5H), 7.66 (d, 2H, J=5.41 Hz). MS(ES) m/z 445.3; (MH.sup.+); HRMS
for C.sub.24H.sub.32SN.sub.2O.sub.4: 444.2082.
INTERMEDIATE 8
[0178]
N-Benzyl-N-(tert-butylcarbonyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8--
yl)benzenesulfonamide
[0179] The title compound was prepared according to the procedure
of Intermediate 3 as a yellow solid. H.sup.1 NMR (CDCl.sub.3)
.delta. 1.34 (s, 9H), 1.78 (t, 4H, J=5.82 Hz), 3.48 (t, 4H, J=5.82
Hz), 3.99 (s, 4H), 5.09 (s, 2H), 6.81 (t, 2H, J=4.83 Hz), 7.35 (m,
5H), 7.50 d, 2H, =4.97 Hz). MS(ES) m/z 489.0; (MH.sup.+); HRMS for
C.sub.25H.sub.32SN.sub.2O.sub- .6: 488.1977.
INTERMEDIATE 9
[0180]
N-Benzyl-N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0181] The title compound was prepared from Intermediate 7
according to the procedure of Intermediate 5 as a yellow solid.
H.sup.1 NMR (CDCl.sub.3) .delta. 0.75 (t, 3H, J=7.26 Hz), 1.12 (m,
2H), 1.32 (m, 2H), 2.59 (t, 4H, J=6.09 Hz), 3.08 (t, 2H, J=7.77
Hz), 3.76 (t, 4H, J=6.18 Hz), 4.32 (s, 2H), 6.94 (d, 2H, J=5.31
Hz), 7.31 (m, 5H), 7.72 (d, 2H, J=5.41 Hz). MS(ES) m/z 401.5;
(MH.sup.+); HRMS for C.sub.22H.sub.28SN.sub.2O.sub.3:
INTERMEDIATE 10
[0182]
N-Butyl-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonamide
[0183] The title compound was prepared from
N-butyl-4-fluoro-benzenesulfon- amide) according to the procedure
of Intermediate 3 as a white solid; mp 122-124.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 0.85 (t, J=7.23 Hz, 3H), 1.21-1.30 (m,
2H), 1.32-1.49 (m, 2H), 1.65 (s, 1H), 1.80 (t, J=5.79 Hz, 4H), 2.90
(q, J=6.75 Hz, 2H), 3.48 (t, J=5.7 Hz, 4H), 4.00 (s, 4H), 6.88-6.93
(m, 2H), 7.67-7.77 (m, 2H); MS (ES) m/z 355.0 (MH.sup.+);
C.sub.17H.sub.26N.sub.2O.sub.4S
INTERMEDIATE 11
[0184] N-Butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0185] The title compound was prepared from
N-butyl-4-(1,4-dioxa-8-aza-spi- ro[4.5]dec-8-yl)-benzenesulfonamide
according to the procedure of Intermediate 5 as an off-white solid;
mp 79-82.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 0.85 (t,
J=7.26 Hz, 3H), 1.23-1.37 (m, 2H), 1.40-1.50 (m, 2H), 1.65 (s, 1H),
2.59 (t, J=6.12 Hz, 4H), 2.92 (q, J=6.69 Hz, 2H), 3.75 (t, J=6.09
Hz, 4H), 6.92-6.97 (m, 2H), 7.70-7.80 (m, 2H); MS (ES) m/z 311.0
(MH.sup.+); HRMS for C.sub.15H.sub.22N.sub.2O.sub.3S: 310.1349
INTERMEDIATE 12
[0186] 1-(4-Fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid
isopropyl ester
[0187] The title compound was prepared from DL-proline,
isopropanol, and 4-fluorobezenesulfonyl chloride according to the
procedure of Intermediate 48 as a clear oil; .sup.1H NMR
(CDCl.sub.3) .delta. 1.21-1.28 (m, 6H), 1.80-1.85 (m, 1H),
1.95-2.10 (m, 3H), 3.31-3.49 (m, 2H), 4.26-4.36 (m, 1H), 4.95-5.08
(m, 1H), 7.15-7.23 (m, 2H), 7.89-8.08 (m, 2H); MS (ES) m/z 315.8
(MH.sup.+); HRMS for C.sub.14H.sub.18FNO.sub.4- S: 338.0830 (M+
Na)
INTERMEDIATE 13
[0188]
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolid-
ine-2-carboxylic acid isopropyl ester
[0189] The title compound was prepared with
1-(4-fluoro-benzenesulfonyl)-p- yrrolidine-2-carboxylic acid
isopropyl ester () according to the procedure of Intermediate 3 as
a clear oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.23-1.28 (m, 6H),
1.80-1.85 (t, J=5.82 Hz, 4H), 1.91-2.05 (m, 3H), 3.24-3.29 (m, 2H),
3.42-3.51 (m, 4H), 4.00 (s, 4H), 4.19-4.25 (m, 1H), 4.96-5.09 (m,
2H), 6.88-6.93 (m, 2H), 7.66-7.74 (m, 2H); MS (ES) m/z 438.9
(MH.sup.+); HRMS for C.sub.21H.sub.30N.sub.2O.sub.6S: 439.1896
(MH.sup.+)
INTERMEDIATE 14
[0190]
1-[4-(4-Oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxyl-
ic acid isopropyl ester
[0191] The title compound was prepared with
1-[4-(1,4-dioxa-8-aza-spiro[4.-
5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid
isopropyl ester () according to the procedure of Intermediate 5 as
a white solid; mp 97-101.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 1.23-1.28 (m, 6H), 1.75-1.80 (m, 1H), 1.94-2.07 (m, 3H),
2.58 (t, J=6.3 Hz, 4H), 3.27-3.36 (m, 1H), 3.42-3.51 (m, 1H), 3.75
(t, 6.09 Hz, 4H), 4.23-4.28 (m, 1H), 4.97-5.10 (m, 1H), 6.91-6.96
(m, 2H), 7.70-7.84 (m, 2H); MS (ES) m/z 394.9 (MH.sup.+); HRMS for
C.sub.19H.sub.26N.sub.2O.sub.5S: 395.1631 (MH.sup.+)
INTERMEDIATE 15
[0192] 1-(4-Fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid
[0193] To a stirred solution of 2.06 g (6.5 mmol) of
1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid
isopropyl ester () in 10 mL of methanol was added 2.3 mL (13 mmol)
of 5N NaOH. After 2 hours, the solvent was removed in vacuo and the
aqueous residue was acidified with 1N HCl and then extracted twice
with ethyl acetate. The organic layer was dried over magnesium
sulfate and concentrated in vacuo to afford 1.69 g of the title
compound as a white solid; ; mp 145-148.degree. C.; .sup.1H NMR
(DMSO) .delta. 1.56-1.63 (m, 1H), 1.78-2.05 (m, 4H), 3.13-3.21 (m,
1H), 4.10-4.15 (m, 1H), 7.42-7.50 (m, 2H), 7.88-7.95 (m, 2H), 12.75
(bs, 1H); MS (ES) m/z 271.9 (MH.sup.-); HRMS for
C.sub.11H.sub.12N.sub.2FO.sub.4S: 274.0543 (MH.sup.+)
INTERMEDIATE 16
[0194] 1-(4-Fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid
benzyl ester
[0195] HCl gas was bubbled into a solution of 1.49 g of
1-(4-fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid () and 6
mL of benzyl alcohol for 15 minutes and the resulting mixture was
allowed to stir overnight. 10 mL of 2,3-butanediol and a catalytic
amount of DMAP was then added and stirred for 2 days. The solvent
was removed in vacuo and the residue was purified by flash column
chromatography (3:1Hexanes:Ethyl Acetate) to give 1.01 g of the
title compound as a clear gum; .sup.1H NMR (CDCl.sub.3) .delta.
1.74-1.85 (m, 1H), 1.95-2.18 (m, 3H), 3.32-3.58 (m, 2H), 4.40-4.44
(m, 1H), 5.15 (s, 2H), 7.11-7.17 (m, 2H), 7.33-7.41 (m, 5H),
7.84-7.90 (m, 2H); MS (ES) m/z 363.9 (MH.sup.+); HRMS for
C.sub.18H.sub.18FNO.sub.4S: 364.1012 (MH.sup.+)
INTERMEDIATE 17
[0196]
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolid-
ine-2-carboxylic acid benzyl ester
[0197] The title compound was prepared from
1-(4-fluoro-benzenesulfonyl)-p- yrrolidine-2-carboxylic acid benzyl
ester () according to the procedure of Intermediate 3 as a gum;
.sup.1H NMR (CDCl.sub.3) .delta. 1.54-1.62 (m, 1H), 1.67 (t, J=5.64
Hz, 4H), 1.69-1.90 (m, 4H), 3.07-3.15 (m, 1H), 3.35-3.48 (m, 4H),
3.92 (s, 4H), 4.15-4.20 (m, 1H), 5.14 (s, 2H), 7.05 (d, J=9.09 Hz,
2H), 7.22-7.43 (m 5H), 7.58 (d, J=9.00 Hz, 2H); MS (ES) m/z 487.0
(MH.sup.+); HRMS for C.sub.25H.sub.30N.sub.2O.sub.6S: 487.1890
(MH.sup.+)
INTERMEDIATE 18
[0198]
{Butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid benzyl ester
[0199] The title compound was prepared from
N-butyl-4-(4-oxo-piperidin-1-y- l)-benzenesulfonamide () and benzyl
bromoacetate according to the procedure of Intermediate 2 as a gum;
.sup.1H NMR (CDCl.sub.3) .delta. 0.85 (t, J=7.23 Hz, 3H), 1.19-1.32
(m, 2H), 1.43-1.53 (m, 2H), 2.56 (t, J=6.12 Hz, 4H), 3.19 (t,
J=7.47 Hz, 2H), 3.72 (t, J=6.06 Hz, 4H), 4.09 (s, 2H), 5.10 (s,
2H), 6.84-6.89 (m, 2H), 7.29-7.40 (m, 5H), 7.69-7.74 (m, 2H); MS
(ES) m/z 459.4 (MH.sup.+); HRMS for C.sub.25H.sub.30N.sub.2O.-
sub.6S: 459.1945 (MH.sup.+)
INTERMEDIATE 19
[0200] (2S)-1-4-Fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid benzyl ester
[0201] The title compound was prepared from L-proline, benzyl
alcohol, and 4-fluorobezenesulfonyl chloride according to the
procedure of Intermediate 48 as a gum; .sup.1H NMR (CDCl.sub.3)
.delta. 1.80-1.85 (m, 1H), 1.94-2.30 (m, 3H), 3.31-3.51 (m, 2H),
4.42 (dd, J=3.57 Hz, 8.13 Hz, 1H), 5.14 (s, 2H), 6.91-7.17 (m, 2H),
7.32-7.40 (m, 5H), 7.84-7.90 (m, 2H); MS (ES) m/z 363.8 (MH.sup.+);
HRMS for C.sub.18H.sub.18FNO.sub.4S: 364.1011
INTERMEDIATE 20
[0202]
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolid-
ine-2-carboxylic acid methylamide
[0203] 0.57 g of
1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl-
]-pyrrolidine-2-carboxylic acid isopropyl ester () was stirred in
20 mL methyl amine (40% wt in water) at 100.degree. C. in a sealed
tube for 5 days. The methyl amine was allowed to evaporate and the
residual aqueous solution was left to stand overnight uncapped. The
following morning, a white precipitate was present, which was
collected by vacuum filtration. The precipitate was washed with
water and hexanes. The original aqueous solution was then extracted
twice with ethyl acetate. The organic layer was then dried over
sodium sulfate and concentrated in vacuo to afford more product.
0.31 g of the title compound was collected as a white solid; mp
137-139.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 1.52-1.72 (m,
5H), 1.81 (t, J=5.82 Hz, 4H), 2.15-2.20 (m, 1H), 2.86 (d, J=4.95
Hz, 3H), 3.08-3.55 (m, 1H), 3.49-3.55 (m, 4H), 4.00 (s, 4H),
6.89-6.94 (m, 2H), 6.99-7.01 (m, 1H), 7.61-7.73 (m, 2H); MS (ES)
m/z 410.0 (MH.sup.+); HRMS for C.sub.19H.sub.27N.sub.3O.sub.5S:
410.1740
INTERMEDIATE 21
[0204]
(2S)-1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyr-
rolidine-2-carboxylic acid benzyl ester
[0205] The title compound was prepared with
1-(4-fluoro-benzenesulfonyl)-p- yrrolidine-2-carboxylic acid benzyl
ester () according to the procedure of Intermediate 3 as a
colorless gum; .sup.1H NMR (CDCl.sub.3) .delta. 1.67-1.82 (m, 4H),
1.92-2.03 (m, 3H), 3.17-3.36 (m, 3H), 3.42-3.64 (m, 4H), 4.00 (s,
4H), 4.24-4.47 (m, 1H), 5.16 (s, 2H), 6.62-6.91 (m, 2H), 7.29-7.42
(m, 5H), 7.66-7.72 (m, 2H); MS (ES) m/z 487.0 (MH.sup.+); HRMS for
C.sub.25H.sub.30N.sub.2O.sub.6S: 487.1893
INTERMEDIATE 22
[0206]
(2S)-1-[4-(4-Oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-car-
boxylic acid benzyl ester
[0207] The title compound was prepared with
(2S)-1-[4-(1,4-dioxa-8-aza-spi-
ro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid
benzyl ester () according to the procedure of Intermediate 5 as a
gum; .sup.1H NMR (CDCl.sub.3) .delta. 1.65-1.82 (m, 1H), 1.90-2.17
(m, 3H), 2.57 (t, J=6.09 Hz, 4H), 3.28-3.34 (m, 1H), 3.42-3.49 (m,
1H), 3.73 (t, J=6.09 Hz, 4H), 4.35-4.39 (m, 1H), 5.16 (s, 2H),
6.87-6.92 (m, 2H), 7.29-7.40 (m, 5H), 7.73-7.79 (m, 2H); MS (ES)
m/z 442.9 (MH.sup.+); HRMS for C.sub.23H.sub.26N.sub.2O.sub.5S:
443.1631 (MH.sup.+)
INTERMEDIATE 23
[0208]
(2R)-1-[4-(4-Oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-car-
boxylic acid benzyl ester
[0209] The title compound was prepared with
(2R)-1-[4-(1,4-dioxa-8-aza-spi-
ro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid
benzyl ester according to the procedure of Intermediate 5 as a gum;
.sup.1H NMR (CDCl.sub.3) .delta. 1.61-1.82 (m, 1H), 1.92-2.06 (m,
3H), 2.58 (t, J=6.18 Hz, 4H), 3.27-3.35 (m, 1H), 3.42-3.52 (m, 1H),
3.73 (t, J=6.06 Hz, 4H), 4.35-4.39 (dd, J=3.87 Hz, 7.98 Hz, 1H),
5.17 (s, 2H), 6.85-6.92 (m, 2H), 7.29-7.41 (m, 5H), 7.73-7.88 (m,
2H); MS (ES) m/z 442.9 (MH.sup.+); HRMS for
C.sub.23H.sub.26N.sub.2O.sub.5S: 443.1632 (MH.sup.+)
INTERMEDIATE 24
[0210]
8-[4-(Toluene-4-sulfonyl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane
[0211] To a solution of 4-fluorophenyl-4-tolylsulfone (1.25 g, 5
mmol) in N,N'-dimethylpropyleneurea (5 ml) was added
1,4-dioxa-8-aza-spiro[4.5]dec- ane (0.88 g, 6 mmol), and potassium
carbonate (0.83 g, 6 mmol). The mixture was stirred at room
temperature for 4 h and then heated at 70.degree. C. for 18 h. An
additional 0.22 g of 1,4-dioxa-8-aza-spiro[4.5- ]decane was added,
and the reaction was continued for 1 day. The mixture was cooled to
room temperature, and treated with water. The resulting suspension
was filtered, and the precipitate washed with water and methanol,
and dried in vacuo to give 1.80 g of a white solid; m.p.
164-165.degree. C.; MS (ES) m/z 373.9 (MH.sup.+); HRMS (EI) Calcd.
for C.sub.20H.sub.23NO.sub.4S (M.sup.+): 373.1348, Found:
373.1342.
INTERMEDIATE 25
[0212] 1-[4-(Toluene-4-sulfonyl)-phenyl]-piperidin-4-one
[0213] The title compound was prepared according to the procedure
of Intermediate 40 from 2.0 g (4.7 mmol) of
8-[4-(toluene-4-sulfonyl)-phenyl-
]-1,4-dioxa-8-aza-spiro[4.5]decane, yielding 1.42 g of a white
solid; m.p. 159-160.degree. C.; MS (ES) m/z 329.9 (MH.sup.+); HRMS
(EI) Calcd. for C.sub.18H.sub.19NO.sub.3S (M.sup.+): 329.1086,
Found: 329.1073.
INTERMEDIATE 26
[0214]
2-But-2-ynyl-2-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfo-
nyl]-hex-4-ynoic acid tert-butyl ester
[0215] The title compound was prepared according to the procedure
of Intermediate 24 from 0.53 g (3.6 mmol) of
1,4-dioxa-8-aza-spiro[4.5]decan- e and 1.13 g (3.0 mmol) of
2-but-2-ynyl-2-[4-fluorobenzenesulfonyl]-hex-4-- ynoic acid
tert-butyl ester, yielding 1.52 g of a colorless foam; MS (ES) m/z
502.3 (MH.sup.+); HRMS (EI) Calcd. for C.sub.27H.sub.35NO.sub.6S
(M.sup.+): 501.2185, Found: 501.2177.
INTERMEDIATE 27
[0216]
2-But-2-ynyl-2-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-hex-4-yno-
ic acid tert-butyl ester
[0217] The title compound was prepared according to the procedure
of Intermediate 40 from 1.40 g (2.8 mmol) of
2-but-2-ynyl-2-[4-(1,4-dioxa-8--
aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-hex-4-ynoic acid
tert-butyl ester, yielding 1.19 g of a white solid; m.p.
128-130.degree. C.; MS (ES) m/z 458.2 (MH.sup.+); HRMS (EI) Calcd.
for C.sub.25H.sub.31NO.sub.5S (M.sup.+): 457.1923, Found:
457.1919.
INTERMEDIATE 28
[0218] 4-Fluoro-N-(2-hydroxyethyl)-benzenesulfonamide
[0219] The title compound was prepared according to the procedure
of Intermediate 33 from 3.97 g (20 mmol) of 4-fluorobenzenesulfonyl
chloride and 3.11 g (50 mmol) of ethanolamine, yielding 3.0 g of a
white solid; m.p. 77-78.degree. C.; MS (ES) m/z 219.8 (MH.sup.+);
HRMS (EI) Calcd. for C.sub.8H.sub.10FNO.sub.3S (M.sup.+): 219.0366,
Found: 219.0369.
INTERMEDIATE 29
[0220]
4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-N-(2-hydroxyethyl)-benzenesu-
lfonamide
[0221] The title compound was prepared according to the procedure
of Intermediate 24 from 2.28 g (15.6 mmol) of
1,4-dioxa-8-aza-spiro[4.5]deca- ne and 2.85 g (13.0 mmol) of
4-fluoro-N-(2-hydroxyethyl)-benzenesulfonamid- e, yielding 3.0 g of
a colorless gum; MS (ES) m/z 343.2 (MH.sup.+); HRMS (EI) Calcd. for
C.sub.15H.sub.22N.sub.2O.sub.5S (M.sup.+): 342.1249, Found:
342.1235.
INTERMEDIATE 30
[0222]
N-(2-Hydroxyethyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0223] The title compound was prepared according to the procedure
of Intermediate 40 from 2.23 g (6.5 mmol) of
4-(1,4-dioxa-8-aza-spiro[4.5]de-
c-8-yl)-N-(2-hydroxyethyl)-benzenesulfonamide, yielding 1.88 g of a
colorless gum; MS (ES) m/z 299.1 (MH.sup.+); HRMS (EI) Calcd. for
C.sub.13H.sub.18N.sub.2O.sub.4S (M.sup.+): 298.0988, Found:
298.0974.
INTERMEDIATE 31
[0224]
8-[4-(Piperidine-1-sulfonyl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]deca-
ne
[0225] The title compound was prepared with
N-piperidine-4-fluoro-benzenes- ulfonamide according to the
procedure of Intermediate 37 as a white solid; .sup.1H NMR
(CDCl.sub.3) .delta. 1.36-1.44 (m, 2H), 1.59-1.67 (m, 4H), 1.81 (t,
J=5.79 Hz, 4H), 2.95 (t, J=5.37 Hz, 4H), 3.49 (t, J=5.7 Hz, 4H),
4.00 (s, 4H), 6.89-6.93 (m, 2H), 7.56-7.61 (m, 2H); MS (ES) m/z
367.32 (MH.sup.+); HRMS for C.sub.18H.sub.26N.sub.2O.sub.4S:
367.1683
INTERMEDIATE 32
[0226]
8-[4-(Pyrrolidine-1-sulfonyl)-phenyl]-1,4-dioxa-8-aza-spiro[4.5]dec-
ane
[0227] The title compound was prepared with
N-pyrrolidine-4-fluoro-benzene- sulfonamide according to the
procedure of Intermediate 37 as a white needles; .sup.1H NMR
(CDCl.sub.3) .delta. 1.72-1.77 (m, 4H), 1.79-1.83 (m, 4H),
3.14-3.23 (m, 4H), 3.47-3.51 (m, 4H), 4.00 (s, 4H), 6.89-6.95 (m,
2H), 7.61-7.72 (m, 2H); MS (ES) m/z 353.29 (MH.sup.+); HRMS for
C.sub.17H.sub.24N.sub.2O.sub.4S: 353.1527
INTERMEDIATE 33
[0228] N-Cyclopropylmethyl-4-fluoro-benzenesulfonamide
[0229] To a stirred solution of 2 mL (23 mmol) of aminomethyl
cyclopropane in 25 mL methylene chloride was added 4.8 mL (28 mmol)
of diisopropylethyl amine. After 10 minutes of stirring, 4.49 g (23
mmol) of 4-fluorobenzene sulfonyl chloride was added and the
mixture was allowed to stir for 4 hours. The reaction mixture was
quenched with water and the organic layer was washed twice with 1N
HCl, twice with water, dried over magnesium sulfate and then
concentrated in vacuo. Then the solid was dried under vacuum to
give 4.65 g of the title compounds as an off white solid; .sup.1H
NMR (CDCl.sub.3) .delta. 0.08-0.13 (m, 2H), 0.45-0.51 (m, 2H),
0.83-0.94 (m, 1H), 2.86 (t, J=6.9 Hz, 2H), 4.66-4.71 (m, 1H),
7.12-7.23 (m, 2H), 7.85-7.92 (m, 2H); MS (ES) m/z 218.23
(MH.sup.+); HRMS for C.sub.10H.sub.12FNO.sub.2S: 218.0637
INTERMEDIATE 34
[0230] 1-[4-(Pyrrolidine-1-sulfonyl)-phenyl]-piperidin-4-one
[0231] The title compound was prepared with
8-[4-(pyrrolidine-1-sulfonyl)--
phenyl]-1,4-dioxa-8-aza-spiro[4.5]decane according to the procedure
of Intermediate 40 as a fluffy beige solid; .sup.1H NMR
(CDCl.sub.3) .delta. 1.70-1.79 (m, 4H), 2.59 (t, J=6.18 Hz, 4H),
3.20-3.29 (m, 4H), 3.75 (t, J=6.09 Hz, 4H), 6.86-6.97 (m, 2H),
7.70-7.76 (m, 2H); MS (ES) m/z 230.2 (MH.sup.+); HRMS for
C.sub.15H.sub.20N.sub.2O.sub.3S: 230.0645
INTERMEDIATE 35
[0232] 1-[4-(Piperidine-1-sulfonyl)-phenyl]-piperidin-4-one
[0233] The title compound was prepared with
8-[4-(piperidine-1-sulfonyl)-p-
henyl]-1,4-dioxa-8-aza-spiro[4.5]decane according to the procedure
of Intermediate 40 as an off white solid; .sup.1H NMR (CDCl.sub.3)
.delta. 1.37-1.45 (m, 2H), 1.60-1.68 (m, 4H), 2.59 (t, J=6.18 Hz,
4H), 2.97 (t, J=5.4 Hz, 4H), 3.75 (t, J=6.09 Hz, 4H), 6.90-6.97 (m,
2H), 7.61-7.68 (m, 2H); MS (ES) m/z 323.3 (MH.sup.+); HRMS for
C.sub.16H.sub.22N.sub.2O.sub.- 3S: 323.1398
INTERMEDIATE 36
[0234]
4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-N-isobutyl-benzenesulfonamid-
e
[0235] The title compound was prepared with
4-fluoro-n-isobutyl-benzenesul- fonamide according to the procedure
of Intermediate 37 as a light yellow solid; .sup.1H NMR
(CDCl.sub.3) .delta. 0.86-0.89 (m, 6H), 1.78 (t, J=5.76 Hz, 4H),
2.69-2.82 (m, 3H), 2.95 (s, 1H), 3.49 (t, J=5.79 Hz, 4H), 4.00 (s,
4H), 6.88-6.94 (m, 2H), 7.66-7.71 (m, 2H); MS (ES) m/z 355.3
(MH.sup.+)
INTERMEDIATE 37
[0236]
N-Cyclopropylmethyl-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenes-
ulfonamide
[0237] A mixture of 2.5 g (11 mmol)
n-cyclopropylmethyl-4-fluoro-benzene-s- ulfonamide, 1.87 g (13
mmol) 1,4 dioxa-8-azaspiro[4,5]decane and 1.81 g (13 mmol)
potassium carbonate was heated at 65.degree. C. in 6 mL
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 3 mL
acetonitrile overnight. The reaction mixture was quenched with
water and extracted twice with ethyl acetate. The organic layer was
then washed twice with 1N HCl, twice with water, dried over sodium
sulfate and then concentrated in vacuo. After drying overnight on a
vacuum line, 3.33 g of the title compound was isolated as a yellow
solid; .sup.1H NMR (CDCl.sub.3) .delta. 0.51 (m, 2H), 0.81-0.94 (m,
2H), 1.80 (t, J=5.85 Hz, 4H), 2.77-2.84 (m, 2H), 2.92 (s, 1H), 3.48
(t, J=5.76 Hz, 4H), 4.00 (s, 4H), 4.32-4.37 (m, 1H), 6.88-6.93 (m,
2H), 7.66-7.71 (m, 2H); MS (ES) m/z 353.3 (MH.sup.+); HRMS for
C.sub.17H.sub.24N.sub.2O.sub.4S: 353.1539
INTERMEDIATE 38
[0238]
{[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-methyl-am-
ino}-acetic acid ethyl ester
[0239] The title compound was prepared with
[(4-fluoro-benzenesulfonyl)-me- thyl-amino]-acetic acid ethyl ester
according to the procedure of Intermediate 37 as a red oil; .sup.1H
NMR (CDCl.sub.3) .delta. 1.25 (t, J=5.58 Hz, 3H), 1.80 (t, J=5.85
Hz, 3H), 2.84 (s, 1H), 2.92 (s, 1H), 3.53 (m, 4H), 3.92 (s, 3H),
4.00 (s, 4H), 4.13 (q, J=5.22 Hz, 2H), 6.88-6.95 (m, 2H), 7.58-7.67
(m, 2H); MS (ES) m/z 399.2 (MH.sup.+); HRMS for
C.sub.18H.sub.26N.sub.2O.sub.6S: 399.1585
INTERMEDIATE 39
[0240] N-Isobutyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0241] The title compound was prepared with
4-(1,4-dioxa-8-aza-spiro[4.5]d-
ec-8-yl)-N-isobutyl-benzenesulfonamide according to the procedure
of Intermediate 40 as an beige solid; .sup.1H NMR (CDCl.sub.3)
.delta. 0.87 (d, J=6.72 Hz, 6H), 1.63-1.81 (m, 1H), 2.59 (t, J=6.15
Hz, 4H), 2.75 (q, J=6.75 Hz, 2H), 2.92 (s, 1H), 3.75 (t, J=6.09 Hz,
4H), 6.86-6.97 (m, 2H), 7.70-7.78 (m, 2H); MS (ES) m/z 311.3
(MH.sup.+); HRMS for C.sub.15H.sub.22N.sub.2O.sub.3S: 311.1420
INTERMEDIATE 40
[0242]
N-Cyclopropylmethyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0243] A solution of 3 g (8.5 mmol)
n-cyclopropylmethyl-4-(1,4-dioxa-8-aza-
-spiro[4.5]dec-8-yl)-benzenesulfonamide in 40 mL acetone and 40 mL
10% sulfuric acid in water was stirred for 3 days. The solvent was
removed in vacuo and the resulting mix was quenched with water and
neutralized with 10% sodium carbonate. The aqueous mixture was
extracted twice with methylene chloride. The organic layer was
dried over magnesium sulfate and concentrated in vacuo. The
resulting solid was then triturated with hexanes and ether. After
drying via high vacuum, 2.56 g of the title compound was isolated
as a beige solid; .sup.1H NMR (CDCl.sub.3) .delta. 0.81-0.97 (m,
2H), 1.26 (s, 1H), 2.59 (t, J=6.15 Hz, 4H), 2.77-2.87 (m, 4H), 2.92
(s, 1H), 3.75 (t, J=6.06 Hz, 4H), 6.89-6.96 (m, 2H), 7.73-7.78 (m,
2H); MS (ES) m/z 309.3 (MH.sup.+); HRMS for
C.sub.15H.sub.20N.sub.2O.- sub.3S: 309.1251
INTERMEDIATE 41
[0244]
{Methyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid
[0245] The title compound was prepared with
{[4-(1,4-dioxa-8-aza-spiro[4.5-
]dec-8-yl)-benzenesulfonyl]-methyl-amino}-acetic acid ethyl ester
according to the procedure of Intermediate 40 as a red gum; .sup.1H
NMR (CDCl.sub.3) .delta. 2.61 (t, J=6.12 Hz, 4H), 2.87 (s, 1H),
2.92 (s, 1H), 3.77 (t, J=6.09 Hz, 4H), 3.97 (s, 2H), 6.91-6.99 (m,
2H), 7.69-7.73 (m, 2H); MS (ES) m/z 327.2 (MH.sup.+); HRMS for
C.sub.14H.sub.18N.sub.2O.sub.- 5S: 327.1019
INTERMEDIATE 42
[0246]
{Methyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid ethyl ester
[0247] A solution of 0.53 g (1.6 mmol)
{methyl-[4-(4-oxo-piperidin-1-yl)-b- enzenesulfonyl]-amino}-acetic
acid in 8 mL anhydrous tetrahydrofuran was treated with 0.32 g (2.0
mmol) 1,1'-carbonyl-diimidazole. After stirring for 45 minutes, 1
mL of ethanol was added. The resulting mixture was then permitted
to stir overnight. The solvent was removed in vacuo and the residue
was dissolved in ethyl acetate. The organics were washed twice with
saturated sodium bicarbonate, twice with water, dried over sodium
sulfate and concentrated in vacuo. After drying via high vacuum
overnight, 0.76 g of the title compound was isolated as a red
solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.23-1.29 (m, 3H), 2.59 (t,
J=6.15 Hz, 4H), 2.87 (s, 1H), 3.76 (t, J=6.09 Hz, 4H), 3.96 (s,
2H), 4.11-4.18 (m, 2H), 6.89-6.96 (m, 2H), 7.67-7.75 (m, 2H); MS
(ES) m/z 355.3 (MH.sup.+); HRMS for
C.sub.16H.sub.22N.sub.2O.sub.5S: 355.1332
INTERMEDIATE 43
[0248]
{Butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid ethyl ester
[0249] The title compound was prepared with
N-butyl-4-(4-oxo-piperidin-1-y- l)-benzenesulfonamide and ethyl
bromoacetate according to the procedure of Intermediate 2 as a
yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 0.88 (t, J=7.29 Hz,
3H), 1.23 (t, J=7.11 Hz, 3H), 1.19-1.35 (m, 2H), 1.48-1.56 (m, 2H),
2.58 (t, J=6.18 Hz, 4H), 3.20 (t, J=7.47 Hz, 2H), 3.74 (t, J=6.09
Hz, 4H), 4.03 (s, 2H), 4.13 (q, J=7.14 Hz, 2H), 6.89-6.95 (m, 2H),
7.72-7.78 (m, 2H); MS (ES) m/z 397.2 (MH.sup.+); HRMS for
C.sub.19H.sub.28N.sub.2O.sub.5S: 397.1791
INTERMEDIATE 44
[0250]
4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-N-isopropyl-benzenesulfonami-
de
[0251] The title compound was prepared with
4-fluoro-N-isopropyl-benzenesu- lfonamide according to the
procedure of Intermediate 37 as a colorless oil; .sup.1H NMR
(CDCl.sub.3) .delta. 1.06 (d, J=6.54 Hz, 6H), 1.81 (t, J=5.85 Hz,
4H), 1.92-2.01 (m, 1H), 2.92 (s, 1H), 3.25 (t, J=5.94 Hz, 4H), 4.00
(s, 4H), 6.89-6.94 (m, 2H), 7.68-7.72 (m, 2H); MS (ES) m/z 341.2
(MH.sup.+); HRMS for C.sub.16H.sub.24N.sub.2O.sub.4S: 341.1526
INTERMEDIATE 45
[0252]
{Cyclopropylmethyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino-
}-acetic acid ethyl ester
[0253] The title compound was prepared with
n-cyclopropylmethyl-4-(4-oxo-p- iperidin-1-yl)-benzenesulfonamide
and ethyl bromoacetae according to the procedure of Intermediate 2
as a yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 0.10 (m, 2H),
0.50-0.54 (m, 2H), 0.82-0.94 (m, 1H), 1.23 (t, J=7.14 Hz, 3H), 2.58
(t, J=6.18 Hz, 4H), 3.13 (d, J=6.96 Hz, 2H), 3.74 (t, J=6.09 Hz,
4H), 4.13 (q, J=7.14 Hz, 2H), 4.21 (s, 2H), 6.89-6.94 (m, 2H),
7.73-7.78 (m, 2H); MS (ES) m/z 395.5 (MH.sup.+); HRMS for C.sub.1
9H.sub.26N.sub.2O.sub.5S: 395.1578
INTERMEDIATE 46
[0254]
{Isobutyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid ethyl ester
[0255] The title compound was prepared with
N-isobutyl-4-(4-oxo-piperidin-- 1-yl)-benzenesulfonamide and ethyl
bromoacetae according to the procedure of Intermediate 2 as a
yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 0.90 (d, J=7.29 Hz,
6H), 1.22 (t, J=7.11 Hz, 3H), 1.72-1.89 (m, 1H), 2.58 (t, J=6.12
Hz, 4H), 3.02 (d, J=7.53 Hz, 2H), 3.74 (t, J=6.06 Hz, 4H), 4.00 (s,
4H), 4.11 (q, J=7.14 Hz, 2H), 6.89-6.96 (m, 2H), 7.70-7.76 (m, 2H);
MS (ES) m/z 397.2 (MH.sup.+); HRMS for
C.sub.19H.sub.26N.sub.2O.sub.5S: 397.1702
INTERMEDIATE 47
[0256] N-Isopropyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0257] The title compound was prepared with
4-(1,4-dioxa-8-aza-spiro[4.5]d-
ec-8-yl)-N-isopropyl-benzenesulfonamide according to the procedure
of Intermediate 40 as a white solid; mp 103-105.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 1.09 (d, J=6.48 Hz, 6H), 2.59 (t, J=6.18
Hz, 4H), 3.36-3.43 (m, 1H), 3.47-3.54 (m, 1H), 3.75 (t, J=6.09 Hz,
4H), 6.89-6.96 (m, 2H), 7.71-7.79 (m, 2H); MS (ES) m/z 297.2
(MH.sup.+); HRMS for C.sub.14H.sub.20N.sub.2O.sub.3S: 296.1196
INTERMEDIATE 48
[0258] 1-(4-Fluoro-benzenesulfonyl)-pyrrolidine-(2R)-2-carboxylic
acid ethyl ester
[0259] To 5 g (43 mmol) of D-proline in 20 g (434 mmol) ethanol was
added 100 mL 1N HCl in ether. (mixture should become homogenous
over time) After stirring for 3 days, the solvent was removed in
vacuo. The residue was then dissolved in methylene chloride, which
was then treated with 12 mL (86 mmol) of triethylamine. After 15
minutes, 8.45 g (43 mmol) of 4-fluoro-benzenesulfonyl chloride was
added and the resulting mixture was stirred overnight. The reaction
mixture was quenched with water and the organic layer was washed
twice with saturated sodium carbonate, twice with 1N HCl and twice
with water. After drying over magnesium sulfate, the organics were
concentrated in vacuo and dried via high vacuum to give 11.56 g of
the title compound as a white solid; mp 62-63.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 1.26 (t, J=7.11 Hz, 3H), 1.81-1.86 (m,
1H), 1.95-2.17 (m, 2H), 3.32-3.48 (m, 2H), 4.08-4.24 (m, 2H), 4.37
(q, J=3.99 Hz, 2H), 7.15-7.23 (m, 2H), 7.88-7.98 (m, 2H); MS (ES)
m/z 302.3 (MH.sup.+); HRMS for C.sub.13H.sub.16FNO.sub.4S:
302.2934
INTERMEDIATE 49
[0260] 1-(4-Fluoro-benzenesulfonyl)-pyrrolidine-2-carboxylic acid
ethyl ester
[0261] The title compound was prepared with DL-proline according to
the procedure of Intermediate 48 as a white semi-solid; .sup.1H NMR
(CDCl.sub.3) .delta. 1.26 (t, J=7.11 Hz, 3H), 1.81-1.85 (m, 1H),
1.95-2.13 (m, 2H), 3.32-3.48 (m, 2H), 4.08-4.24 (m, 2H), 4.34 (q,
J=4.47 Hz, 2H), 7.15-7.23 (m, 2H), 7.89-7.96 (m, 2H); MS (ES) m/z
302.3 (MH.sup.+); HRMS for C.sub.13H.sub.16FNO.sub.4S: 302.0830
INTERMEDIATE 50
[0262] 1-(4-Fluoro-benzenesulfonyl)-pyrrolidine-(2S)-2-carboxylic
acid ethyl ester
[0263] The title compound was prepared with L-proline according to
the procedure of Intermediate 48 as a white solid; mp 58-59.degree.
C.; .sup.1H NMR (CDCl.sub.3) .delta. 1.26 (t, J=7.14 Hz, 3H),
1.81-1.85 (m, 1H), 1.95-2.11 (m, 2H), 3.31-3.48 (m, 2H), 4.09-4.24
(m, 2H), 4.34 (q, J=4.41 Hz, 2H), 7.15-7.23 (m, 2H), 7.88-7.98 (m,
2H); MS (ES) m/z 302.3 (MH.sup.+); HRMS for
C.sub.13H.sub.16FNO.sub.4S: 302.0855
INTERMEDIATE 51
[0264]
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolid-
ine-(2R)-2-carboxylic acid ethyl ester
[0265] The title compound was prepared with
1-(4-fluoro-benzenesulfonyl)-p- yrrolidine-(2R)-2-carboxylic acid
ethyl ester () according to the procedure of Intermediate 37 as a
yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.27 (t, J=7.14 Hz,
3H), 1.76-1.81 (m, 4H), 1.92-1.99 (m, 4H), 3.22-3.31 (m, 3H),
3.42-3.51 (m, 4H), 4.00 (s, 4H), 4.18 (q, J=4.80 Hz, 2H), 6.91 (d,
J=9.03 Hz, 2H), 7.68-7.74 (m, 2H); MS (ES) m/z 425.3 (MH.sup.+);
HRMS for C.sub.20H.sub.28N.sub.2O.sub.6S: 425.1685
INTERMEDIATE 52
[0266]
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolid-
ine-2-carboxylic acid ethyl ester
[0267] The title compound was prepared with
1-(4-fluoro-benzenesulfonyl)-p- yrrolidine-2-carboxylic acid ethyl
ester according to the procedure of Intermediate 37 as a yellow
oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.23-1.29 (m, 3H), 1.78-1.83
(m, 4H), 1.92-2.06 (m, 4H), 3.22-3.32 (m, 3H), 3.44-3.50 (m, 4H),
4.00 (s, 4H), 4.16-4.20 (m, 2H), 6.88-6.94 (m, 2H), 7.68-7.75 (m,
2H); MS (ES) m/z 425.2 (MH.sup.+); HRMS for
C.sub.20H.sub.28N.sub.2O.sub.6S: 425.1661
INTERMEDIATE 53
[0268]
1-[4-(4-Oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-(2R)-2-car-
boxylic acid ethyl ester
[0269] The title compound was prepared with
1-[4-(1,4-dioxa-8-aza-spiro[4.-
5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-(2R)-2-carboxylic acid
ethyl ester according to the procedure of Intermediate 40 as a
yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.27 (t, J=7.14 Hz,
3H), 1.76-1.81 (m, 1H), 1.94-2.10 (m, 2H), 2.61 (t, J=7.44 Hz, 4H),
3.23-3.36 (m, 2H), 3.44-3.49 (m, 2H), 4.17-4.22 (m, 2H), 6.91-6.96
(m, 2H), 7.75-7.81 (m, 2H); MS (ES) m/z 381.2 (MH.sup.+); HRMS for
C.sub.18H.sub.24N.sub.2O.sub.- 5S: 380.1398
INTERMEDIATE 54
[0270]
1-[4-(1,4-Dioxa-8-aza-spiro[4.5]dec-8-yl)-benzenesulfonyl]-pyrrolid-
ine-(2S)-2-carboxylic acid ethyl ester
[0271] The title compound was prepared with
1-(4-fluoro-benzenesulfonyl)-p- yrrolidine-(2S)-2-carboxylic acid
ethyl ester according to the procedure of Intermediate 37 as a
light yellow semi-solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.26 (t,
J=7.11 Hz, 3H), 1.83 (t, J=5.76 Hz, 4H), 1.92-2.01 (m, 3H), 3.25
(t, J=5.94, 4H), 3.42-3.51 (m, 2H), 4.00 (s, 4H), 4.14-4.21 (m,
4H), 6.94 (d, J=8.97 Hz, 2H), 7.71 (d, J=11.94 Hz, 2H); MS (ES) m/z
425.2 (MH.sup.+); HRMS for C.sub.20H.sub.28N.sub.2O.sub.6S:
424.1699
INTERMEDIATE 55
[0272]
1-[4-(4-Oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxyl-
ic acid ethyl ester
[0273] The title compound was prepared with
1-[4-(1,4-dioxa-8-aza-spiro[4.-
5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic acid ethyl
ester according to the procedure of Intermediate 40 as a light
orange oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.22-1.29 (t, 3H),
1.77-1.80 (m, 4H), 2.59 (t, J=6.18 Hz, 4H), 3.25-3.37 (m, 3H), 3.75
(t, J=6.09 Hz, 4H), 4.13-4.22 (m, 2H), 6.90-6.96 (m, 2H), 7.74-7.81
(m, 2H); MS (ES) m/z 381.2 (MH.sup.+); HRMS for
C.sub.18H.sub.24N.sub.2O.sub.5S: 380.9760
INTERMEDIATE 56
[0274]
1-[4-(4-Oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-(2S)-2-car-
boxylic acid ethyl ester
[0275] The title compound was prepared with
1-[4-(1,4-dioxa-8-aza-spiro[4.-
5]dec-8-yl)-benzenesulfonyl]-pyrrolidine-(2S)-2-carboxylic acid
ethyl ester according to the procedure of Intermediate 40 as an
orange oil; .sup.1H NMR (CDCl.sub.3) .delta. 1.27 (t, J=7.11 Hz,
3H), 1.92-2.01 (m, 3H), 2.61 (t, J=6.42 Hz, 4H), 3.24 (t, J=5.91
Hz, 3H), 3.75 (t, J=6.12 Hz, 4H), 4.14-4.23 (m, 2H), 6.91-6.96 (m,
2H), 7.75-7.83 (m, 2H); MS (ES) m/z 381.3 (MH.sup.+); HRMS for
C.sub.18H.sub.24N.sub.2O.sub.5S: 380.9760
INTERMEDIATE 57
[0276] (2S)-2-(4-Fluoro-benzenesulfonylamino)-4-methyl-pentanoic
acid ethyl ester
[0277] The title compound was prepared with L-leucine ethyl ester
hydrochloride and 2.5 equivalents of triethylamine according to the
procedure of Intermediate 33 as a colorless oil; .sup.1H NMR
(CDCl.sub.3) .delta. 0.88-0.93 (m, 6H), 1.11 (t, J=7.14 Hz, 4H),
1.51 (t, J=7.53 Hz, 1H), 1.73-1.87 (m, 1H), 3.84-3.99 (m, 2H), 5.10
(d, J=9.99 Hz, 1H), 7.12-7.20 (m, 2H), 7.80-7.89 (m, 2H); MS (ES)
m/z 318.2 (MH.sup.+); HRMS for C.sub.14H.sub.20FNO.sub.4S:
317.109
INTERMEDIATE 58
[0278] (2S)-2-(4-Fluoro-benzenesulfonylamino)-3-methyl-butyric acid
ethyl ester
[0279] The title compound was prepared with L-valine ethyl ester
hydrochloride and 2.5 equivalents of triethylamine according to the
procedure of Intermediate 33 as a white solid; .sup.1H NMR
(CDCl.sub.3) .delta. 0.87 (d, J=6.87 Hz, 3H), 0.97 (d, J=6.78 Hz,
3H), 1.10 (t, J=7.14 Hz, 4H), 1.97-2.13 (m, 1H), 3.71 (q, J=4.92
Hz, 1H), 3.74-4.01 (m, 2H), 5.10 (d, J=10.02 Hz, 1H), 7.12-7.20 (m,
2H), 7.81-7.88 (m, 2H); MS (ES) m/z 304.1 (MH.sup.+); HRMS for
C.sub.13H.sub.18FNO.sub.4S: 303.0953
INTERMEDIATE 59
[0280]
ethyl(2S)-2-({[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]sulfonyl-
}amino)-4-methylpentanoate
[0281] The title compound was prepared with
(2S)-2-(4-fluoro-benzenesulfon- ylamino)-4-methyl-pentanoic acid
ethyl ester according to the procedure of Intermediate 37 as a
yellow oil; .sup.1H NMR (CDCl.sub.3) .delta. 0.87-0.91 (m, 3H),
1.07-1.13 (m, 4H), 1.48 (t, J=7.23 Hz, 4H), 3.49 (t, J=5.67, 4H),
3.81-3.92 (m, 8H), 4.00 (s, 4H), 4.96 (d, J=10.08 Hz, 1H),
6.86-6.91 (m, 2H), 7.62-7.67 (m, 2H); MS (ES) m/z 441.3 (MH.sup.+);
HRMS for C.sub.21H.sub.32N.sub.2O.sub.6S: 440.1984
INTERMEDIATE 60
[0282]
ethyl(2S)-2-({[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]sulfonyl-
}amino)-3-methylbutanoate
[0283] The title compound was prepared with
(2S)-2-(4-fluoro-benzenesulfon- ylamino)-3-methyl-butyric acid
ethyl ester according to the procedure of Intermediate 37 as a dark
orange oil; .sup.1H NMR (CDCl.sub.3) .delta. 0.87 (d, J=6.81 Hz,
3H), 0.97 (d, J=6.72 Hz, 3H), 1.06-1.13 (m, 3H), 1.79 (t, J=5.67
Hz, 4H), 3.44-3.49 (m, 4H), 3.89-3.92 (m, 2H), 4.00 (s, 4H), 5.03
(d, J=10.05 Hz, 1H), 6.90 (m, J=8.76 Hz, 2H), 7.62-7.68 (m, 2H); MS
(ES) m/z 427.2 (MH.sup.+); HRMS for
C.sub.20H.sub.30N.sub.2O.sub.6S: 426.1822
INTERMEDIATE 61
[0284]
ethyl(2S)-4-methyl-2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amin-
o)pentanoate
[0285] The title compound was prepared with
ethyl(2S)-2-({[4-(1,4-dioxa-8--
azaspiro[4.5]dec-8-yl)phenyl]sulfonyl}amino)-4-methylpentanoate
according to the procedure of Intermediate 40 as an orange oil;
.sup.1H NMR (CDCl.sub.3) .delta. 0.87-0.93 (m, 6H), 1.11 (t, J=7.14
Hz, 3H), 1.45-1.51 (m, 2H), 1.75-1.86 (m, 2H), 2.57 (t, J=6.15 Hz,
4H), 3.73 (t, J=6.09 Hz, 4H), 3.84-4.00 (m, 2H), 5.04 (d, J=10.02
Hz, 1H), 6.88-6.94 (m, 2H), 7.69-7.76 (m, 2H); MS (ES) m/z 397.2
(MH.sup.+); HRMS for C.sub.19H.sub.28N.sub.2O.sub.5S: 396.1685
INTERMEDIATE 62
[0286]
ethyl(2S)-3-methyl-2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amin-
o)butanoate
[0287] The title compound was prepared with
ethyl(2S)-2-({[4-(1,4-dioxa-8--
azaspiro[4.5]dec-8-yl)phenyl]sulfonyl}amino)-3-methylbutanoate
according to the procedure of Intermediate 40 as an orange solid;
mp 77-80.degree. C.; .sup.1H NMR (CDCl.sub.3) .delta. 0.87 (d,
J=6.81 Hz, 3H), 0.98 (d, J=6.78 Hz, 3H), 1.10 (t, J=7.14 Hz, 3H),
2.00-2.10 (m, 2H), 2.57 (t, J=6.15 Hz, 4H), 3.73 (t, J=6.09 Hz,
4H), 3.88-4.00 (m, 2H), 5.04 (d, J=10.02 Hz, 1H), 6.87-6.92 (m,
2H), 7.60-7.75 (m, 2H); MS (ES) m/z 383.3 (MH.sup.+); HRMS for
C.sub.18H.sub.26N.sub.2O.sub.5S: 383.1633
INTERMEDIATE 63
[0288] ethyl
1-{[(4-fluorophenyl)sulfonyl]amino}cyclohexanecarboxylate
[0289] The title compound was prepared with
1-aminocyclohexanecarboxylic acid, with gentle warming to get the
mixture homogenous, according to the procedure of Intermediate 48
as a white solid; mp 96-98.degree. C.; .sup.1H NMR (CDCl.sub.3)
.delta. 1.23 (t, J=7.17 Hz, 3H), 1.26-1.46 (m, 6H), 1.82-1.87 (m,
4H), 4.00 (q, J=7.11 Hz, 2H), 4.79 (s, 1H), 7.12-7.21 (m, 2H),
7.85-7.92 (m, 2H); MS (ES) m/z 330.2 (MH.sup.+); HRMS for
C.sub.15H.sub.20FNO.sub.4S: 329.1082
INTERMEDIATE 64
[0290] ethyl
1-{[(4-fluorophenyl)sulfonyl]amino}cyclopentanecarboxylate
[0291] The title compound was prepared with
1-aminocyclopentanecarboxylic acid, with gentle warming to get the
mixture homogenous, according to the procedure of Intermediate 48
as a white solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.23 (t, J=7.14
Hz, 3H), 1.62-1.71 (m, 4H), 1.90-1.98 (m, 2H), 2.03-2.11 (m, 2H),
4.04 (q, J=7.14 Hz, 2H), 5.09 (s, 1H), 7.12-7.21 (m, 2H), 7.85-7.92
(m, 2H); MS (ES) m/z 316.2 (MH.sup.+); HRMS for
C.sub.14H.sub.18FNO.sub.4S: 315.0932
INTERMEDIATE 65
[0292] ethyl
1-({[4-(1,4-dioxa-8-azaspiro[4.5]dec-8)phenyl]sulfonyl}amino)-
-cyclopentanecarboxylate
[0293] The title compound was prepared with ethyl
1-{[(4-fluorophenyl)sulf- onyl]-amino}cyclo-pentanecarboxylate
according to the procedure of Intermediate 37 as a light yellow
solid; .sup.1H NMR (CDCl.sub.3) .delta. 1.21 (t, J=7.14 Hz, 3H),
1.64-1.69 (m, 4H), 1.79 (t, J=5.7 Hz, 4H), 1.90-2.10 (m, 6H), 3.48
(t, J=5.79 Hz, 4H), 3.97-4.04 (m, 2H), 4.00 (s, 4H), 4.99 (s, 1H),
6.85-6.91 (m, 2H), 7.60-7.71 (m, 2H); MS (ES) m/z 439.2 (MH.sup.+);
HRMS for C.sub.21H.sub.30N.sub.2O.sub.6S: 438.1812
INTERMEDIATE 66
[0294] ethyl
1-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)cyclopentan-
ecarboxylate
[0295] The title compound was prepared with ethyl
1-({[4-(1,4-dioxa-8-azas-
piro[4.5]-dec-8)phenyl]sulfonyl}amino)cyclopentanecarboxylate
according to the procedure of Intermediate 40 as a yellow gum;
.sup.1H NMR (CDCl.sub.3) .delta. 1.24 (t, J=7.14 Hz, 3H), 1.57-1.69
(m, 4H), 1.90-1.96 (m, 2H), 1.97-2.11 (m, 2H), 2.58 (t, J=6.09 Hz,
4H), 3.74 (t, J=6.06 Hz, 4H), 4.04 (q, J=7.14 Hz, 2H), 5.03 (s,
1H), 6.86-6.93 (m, 2H), 7.72-7.78 (m, 2H); MS (ES) m/z 395.2
(MH.sup.+); HRMS for C.sub.19H.sub.26N.sub.2O.sub.5S: 395.1631
INTERMEDIATE 67
[0296] ethyl
1-({[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-I)phenyl]sulfonyl}amin-
o)cyclohexanecarboxylate
[0297] The title compound was prepared with ethyl
1-{[(4-fluorophenyl)sulf- onyl]-amino}cyclohexanecarboxylate
according to the procedure of Intermediate 37 as a yellow gum;
.sup.1H NMR (CDCl.sub.3) .delta. 1.20-1.29 (m, 3H), 1.44-1.47 (m,
8H), 1.77-1.85 (m, 6H), 3.48 (t, J=5.7 Hz, 4H), 3.98 (q, J=7.59 Hz,
2H), 4.00 (s, 4H), 4.72 (s, 1H), 6.85-6.91 (m, 2H), 7.65-7.71 (m,
2H); MS (ES) m/z 453.2 (MH.sup.+); HRMS for
C.sub.22H.sub.32N.sub.2O.sub.6S: 453.2054
INTERMEDIATE 68
[0298] ethyl
1-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)cyclohexane-
carboxylate
[0299] The title compound was prepared with ethyl
1-({[4-(1,4-dioxa-8-azas-
piro[4.5]dec-8-l)phenyl]sulfonyl}amino)cyclohexanecarboxylate
according to the procedure of Intermediate 40 as a white solid;
.sup.1H NMR (CDCl.sub.3) .delta. 1.23 (t, J=7.11 Hz, 3H), 1.26-1.47
(m, 6H), 1.83-1.87 (m, 4H), 2.58 (t, J=6.12 Hz, 4H), 3.74 (t,
J=6.03 Hz, 4H), 4.01 (q, J=7.14 Hz, 2H), 4.75 (s, 1H), 7.12-7.21
(m, 2H), 7.85-7.92 (m, 2H); MS (ES) m/z 409.3 (MH.sup.+); HRMS for
C.sub.20H.sub.28N.sub.2O.sub.5S: 409.1788
INTERMEDIATE 69
[0300] ethyl
(isopropyl{[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)acet-
ate
[0301] The title compound was prepared with
N-isopropyl-4-(4-oxo-piperidin- -1-yl)-benzenesulfonamide according
to the procedure of Intermediate 2 as a yellow oil; .sup.1H NMR
(CDCl.sub.3) .delta. 1.02-1.10 (m, 6H), 1.25-1.33 (m, 3H),
2.56-2.61 (m, 4H), 3.38-3.50 (m, 1H), 3.74 (t, J=6.06 Hz, 4H),
3.89-3.97 (m, 2H), 4.16-4.28 (m, 2H), 6.89-7.18 (m, 2H), 7.71-7.79
(m, 1H), 7.86-7.91 (m, 1H); MS (ES) m/z 383.3 (MH.sup.+); HRMS for
C.sub.18H.sub.26N.sub.2O.sub.5S: 383.1630
INTERMEDIATE 70
[0302] N-Benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide
[0303] The title compound was prepared from Intermediate 8,
N-Benzyl-N-(tert-butylcarbonyl)-4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)ben-
zenesulfonamide, according to the procedure of Intermediate 5 as a
white solid; mp 136-140.degree. C.; MS (ES) m/z 345.0 (MH.sup.+);
HRMS (EI) for C.sub.18H.sub.20N.sub.2O.sub.3S: 344.1166.
INTERMEDIATE 71
[0304] (3,4-Dimethoxyphenyl)[(4-fluorophenyl)sulfonyl]carbamic
acid, tert-butyl ester
[0305] The title compound was prepared from Intermediate 1,
N-(3,4-dimethoxy-phenyl)-4-fluoro-benzenesulfonamide, according to
the procedure of Intermediate 6 as a tan solid; mp 99-102.degree.
C.; MS (ES) m/z 412.0 (MH.sup.+); HRMS (EI) for
C.sub.19H.sub.22FNO.sub.6S: 344.1166.
INTERMEDIATE 72
[0306]
(3,4-Dimethoxyphenyl)[[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-
sulfonyl]carbamic acid, tert-butyl ester
[0307] The title compound was prepared from Intermediate 71,
(3,4-dimethoxy-phenyl)[(4-fluorophenyl)sulfonyl]carbamic acid,
tert-butyl ester, according to the procedure of Intermediate 3 as a
gum; MS (ES) m/z 434.9 (M-BOC+H.sup.+).
INTERMEDIATE 73
[0308]
N-(3,4-Dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamid-
e
[0309] The title compound was prepared from Intermediate 72,
(3,4-dimethoxyphenyl)-[[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]sulfo-
nyl]carbamic acid, tert-butyl ester, according to the procedure of
Intermediate 5 as a yellow solid; mp 50-56.degree. C.; MS (ES) m/z
391.0 (MH.sup.+); HRMS (EI) for C.sub.19H.sub.22N.sub.2O.sub.5S:
390.1246.
[0310] The following procedures describe the preparation of
representative examples of this invention.
EXAMPLE 1
[0311]
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-{4-[2-hydroxy-3-(2-oxo-2,3-dihy-
dro-1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonam-
ide
[0312] Sodium Triacetoxyborohydride (0.015 g, 0.72 mM) was added to
a solution of
4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol--
2-one (0.08 g, 0.36 mM),
N-Benzyl-N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperi-
din-1-yl)-benzenesulfonamide(0.19 g, 0.39 mM), and acetic acid
(0.025 ml, 0.43 mM) in anhydrous dimethylforamide (5 ml). The
reaction was stirred overnight. The reaction was quenched with 50%
H.sub.2O/sat. NaHCO.sub.3aq. (20 ml). The solids were captured on a
filter and washed with ethyl acetate, diethyl ether, and hexanes to
afford 0.075 g of the desired product as a brown solid. .sup.1H NMR
(DMSO) .delta. 1.31 (m, 2H), 1.89 (m, 2H), 2.71 (m, 2H), 2.87 (m,
3H), 3.53 (s, 3H), 3.67 (s, 3H), 3.87 (m, 4H), 3.98 (m, 1H), 4.67
(s, 2H), 4.95 (bs, 1H), 6.44 (s, 1H), 6.59 (m, 2H), 6.79 (m, 2H),
7.05 (d, 2H, J=8.7 Hz), 7.25 (m, 6H), 7.41 (d, 2H, J=8.4 Hz), 10.59
(bs, 1H), 10.72 (bs, 1H); MS (ES) m/z: 688.1 (MH.sup.+); HRMS for
C.sub.36H.sub.41N.sub.5O.sub.7S: 688.2799 (MH.sup.+)
EXAMPLE 2
[0313]
N-Benzyl-N-butyl-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzo-
imidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide
[0314] The title compound was prepared from
4-((2S)-3-Amino-2-hydroxy-prop- oxy)-1,3-dihydrobenzoimidazol-2-one
and Reference Example 9 according to the procedure of Example 1 as
a brown solid. .sup.1H NMR (DMSO) .delta. 0.67 (t, 3H, J=7.17 Hz),
1.04 (m, 2H), 1.24 (m, 2H), 1.37 (m, 2H), 1.90 (m, 2H), 2.73 (m,
2H), 2.84 (m, 2H), 2.99 (m, 4H), 3.87 (m, 3H), 4.03 (M, 1H), 4.21
(s, 2H), 5.07 (bs, 1H), 6.61 (m, 1H), 6.84 (t, 1H, J=8.1 Hz), 7.07
(d, 2H, J=9.0 Hz), 7.32 (m, 6H), 7.59 (d, 2H, J=8.7 Hz), 10.59 (bs,
1H), 10.72 (bs, 1H); MS (ES) m/z: 608.3 (MH.sup.+); HRMS for
C.sub.32H.sub.41N.sub.5O.sub.5S: 608.2915 (MH.sup.+)
EXAMPLE 3
[0315]
N-Benzyl-N-butyl-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamin-
o-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide
[0316] The title compound was prepared from
N-[5-(2-Amino-1-hydroxy-ethyl)-
-2-hydroxy-phenyl]-methanesulfonamide and Reference Example 9
according to the procedure of Example 1 as an off-white solid.
.sup.1H NMR (DMSO) .delta. 0.67 (t, 3H, J=7.08 Hz), 1.06 (m, 2H),
1.22 (m, 2H), 1.36 (m, 2H), 1.89 (m, 2H), 2.69 (m, 3H), 2.92 (s,
3H), 2.99 (m, 2H), 3.69 (m, 2H), 3.85 (m, 2H), 4.21 (s, 2H), 4.52
(m, 1H), 6.82 (d, 1H, J=11.52 Hz), 7.03 (d, 2H, J=8.1 Hz), 7.19 (s,
1H), 7.32 (m, 6H), 7.61 (d, 2H, J=8.7 Hz); MS (ES) m/z 631.2
(MH.sup.+); HRMS for C.sub.31H.sub.42N.sub.4O.sub.- 6S.sub.2:
631.2626 (MH.sup.+)
EXAMPLE 4
[0317]
N-Benzyl-4-{4-[2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yl-
oxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide
[0318] The title compound was prepared from
4-((2S)-3-Amino-2-hydroxy-prop- oxy)-1,3-dihydrobenzoimidazol-2-one
and Reference Example 70,
N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to
the procedure of Example 1 as a grey solid. .sup.1H NMR (DMSO)
.delta. 1.37 (m, 2H), 1.90 (m, 2H), 2.73 (m, 2H), 2.84 (m, 2H),
2.99 (m, 4H), 3.87 (m, 3H), 4.03 (m, 1H), 5.07 (bs, 1H), 6.67 (m,
1H), 6.85 (t, 1H, J=8.1 Hz), 7.07 (d, 2H, J=9.0 Hz), 7.32 (m, 6H),
7.59 (d, 2H, J=8.7 Hz), 10.59 (bs, 1H), 10.72 (bs, 1H); MS (ES)
m/z: 552.1 (MH.sup.+); HRMS for C.sub.28H.sub.33N.sub.5O.sub.5S:
552.2267 (MH.sup.+)
EXAMPLE 5
[0319]
N-Benzyl-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl-
)-ethylamino]-piperidin-1-yl}-benzenesulfonamide
[0320] The title compound was prepared from
N-[5-(2-Amino-1-hydroxy-ethyl)-
-2-hydroxyphenyl]-methanesulfonamide and Reference Example 70,
N-benzyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to
the procedure of Example 1 as an off-white solid. .sup.1H NMR
(DMSO) .delta. 1.33 (m, 2H), 1.86 (m, 2H), 2.67 (m, 3H), 2.89 (s,
3H), 2.99 (m, 2H), 3.69 (m, 2H), 3.85 (s, 2H), 4.49 (m, 1H), 6.83
(d, 1H, J=6.0 Hz), 7.00 (m, 2H), 7.19 (s, 1H), 7.24 (m, 6H), 7.56
(d, 2H, J=6.6 Hz); MS (ES) m/z: 575.1 (MH.sup.+); HRMS for
C.sub.27H.sub.34N.sub.4O.sub.6S.sub.2: 575.2015 (MH.sup.+)
EXAMPLE 6
[0321]
N-Benzyl-4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-propylamino]-pi-
peridin-1-yl}-benzenesulfonamide
[0322] The title compound was prepared from
4-((2S)-3-Amino-2-hydroxy-prop- oxy)-phenol and Reference Example
70, N-benzyl-4-(4-oxo-piperidin-1-yl)-be- nzenesulfonamide,
according to the procedure of Example 1 as a tan solid. .sup.1H NMR
(DMSO) .delta. 1.27 (m, 2H), 1.86 (m, 2H), 2.75 (m, 3H), 2.91 (t,
2H, J=8.4 Hz), 3.82 (m, 5H), 3.89 (s, 2H), 4.89 (m, 1H), 6.67 (d,
2H, J=6.6 Hz), 6.76 (d, 2H, J=6.6 Hz), 7.02 (d, 2H, J=6.6 Hz), 7.26
(m, 5H), 7.57 (d, 2H, J=6.6 Hz), 7.78 (bs, 1H), 8.87 (bs, 1H); MS
(ES) m/z: 512.1 (MH.sup.+); HRMS for
C.sub.27H.sub.33N.sub.3O.sub.5S: 511.2215 (MH.sup.+)
EXAMPLE 7
[0323]
N-(3,4-Dimethoxy-phenyl)-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro--
1H-benzoimidazol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide
[0324] The title compound was prepared from
4-((2S)-3-Amino-2-hydroxy-prop- oxy)-1,3-dihydrobenzoimidazol-2-one
and Reference Example 73,
N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide,
according to the procedure of Example 1 as a grey solid. .sup.1H
NMR (DMSO) .delta. 1.28 (m, 2H), 1.84 (m, 2H), 2.65 (m, 1H), 2.81
(m, 4H), 3.62 (s, 3H), 3.64 (s, 3H), 3.77 (m, 2H), 3.89 (m, 2H),
4.03 (m, 1H), 4.87 (bs, 1H), 6.59 (m, 4H), 6.74 (d, 1H, J=8.7 Hz),
6.83 (d, 1H, J=8.1 Hz), 6.91 (d, 2H, J=9.0 Hz), 7.45 (d, 2H, J=9.0
Hz), 10.57 (bs, 1H), 10.69 (bs, 1H); MS (ES) m/z: 598.1 (MH.sup.+);
HRMS for C.sub.29H.sub.35N.sub.5O.sub.7S: 598.2296 (MH.sup.+)
EXAMPLE 8
[0325]
N-(3,4-Dimethoxy-phenyl)-4-{4-[2-hydroxy-2-(4-hydroxy-3-methanesulf-
onylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide
[0326] The title compound was prepared from
N-[5-(2-Amino-1-hydroxy-ethyl)-
-2-hydroxyphenyl]-methanesulfonamid, and Reference Example 73,
N-(3,4-dimethoxy-phenyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide,
according to the procedure of Example 1 as a yellow solid; mp
205-218.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
1.15-1.30 (m, 2H), 1.70-1.90 (m, 2H), 2.50-3.00 (m, 5H), 2.89 (s,
3H), 3.62 (s, 3H), 3.65 (s, 3H), 3.65-3.85 (m 2H), 4.40-4.50 (m,
1H), 6.50-7.10 (m, 8H), 7.45 (d, 2H), 9.11 (s, 1H); MS (ES) m/z:
621.0 (MH.sup.+); HRMS Calcd. for
C.sub.28H.sub.37N.sub.4O.sub.8S.sub.2 (MH.sup.+): 621.2053. Found:
621.2058.
EXAMPLE 9
[0327]
4-{4-[(2S)-3-(4-Benzyloxy-phenoxy)-2-hydroxy-propylamino]-piperidin-
-1-yl}-N-(3,4-dimethoxy-phenyl)-benzenesulfonamide
[0328] The title compound was prepared from
1-Amino-3-(4-benzyloxy-phenoxy- )-propan-2-ol and Reference Example
73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo--
piperidin-1-yl)-benzenesulfonamide, according to the procedure of
Example 1 as an off-white solid; mp 113-121.degree. C.; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.15-1.35 (m, 2H), 1.75-1.90 (m,
2H), 2.50-2.90 (m, 5H), 2.89 (s, 3H), 3.61 (s, 3H), 3.64 (s, 3H),
3.64-3.80 (m, 5H), 5.02 (s, 2H), 6.70-7.00 (m, 9H), 7.30-7.70 (m,
7H); MS (ES) m/z : 648.1 (MH.sup.+); HRMS Calcd. for
C.sub.35H.sub.42N.sub.3O.sub.7S (MH.sup.+): 648.2743. Found:
648.2710.
EXAMPLE 10
[0329]
4-{4-[(2S)-3-(9H-Carbazol-4-yloxy)-2-hydroxy-propylamino]-piperidin-
-1-yl}-N-(3,4-dimethoxy-phenyl)-benzenesulfonamide
[0330] The title compound was prepared from
1-Amino-3-(9H-carbazol-4-yloxy- )-propan-2-ol and Reference Example
73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo--
piperidin-1-yl)-benzenesulfonamide, according to the procedure of
Example 1 as an off-white solid; mp 58-64.degree. C.; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.20-1.40 (m, 2H), 1.80-1.95 (m,
2H), 2.60-2.90 (m, 5H), 3.62 (s, 3H), 3.64 (s, 3H), 3.60-3.80 (m,
2H), 4.00-4.20 (m, 3H), 6.40-7.50 (m, 12H), 7.95 (s, 1H), 8.20 (d,
1H), 11.30 (s, 1H); MS (ES) m/z: 631.1 (MH.sup.+); HRMS Calcd. for
C.sub.34H.sub.39N.sub.4O.sub.6S (MH.sup.+): 631.2590. Found:
631.2595.
EXAMPLE 11
[0331]
N-(3,4-Dimethoxy-phenyl)-4-{4-[(2S)-2-hydroxy-3-(4-hydroxy-phenoxy)-
-propylamino]-piperidin-1-yl}-benzenesulfonamide
[0332] The title compound was prepared from
4-((2S)-3-Amino-2-hydroxy-prop- oxy)-phenol and Reference Example
73, N-(3,4-dimethoxy-phenyl)-4-(4-oxo-pi-
peridin-1-yl)-benzenesulfonamide, according to the procedure of
Example 1 as an off-white solid; mp 101-106.degree. C.; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.15-1.30 (m, 2H), 1.70-1.90 (m,
2H), 2.50-2.90 (m, 5H), 3.61 (s, 3H), 3.63 (s, 3H), 3.60-3.90 (m,
5H), 6.45 (dd, 1H), 6.60-6.80 (m, 8H), 6.90 (d, 1H), 7.45 (d, 1H);
MS (ES) m/z: 557.9 (MH.sup.+); HRMS Calcd. for
C.sub.28H.sub.36N.sub.3O.sub.7S (MH.sup.+): 558.2274. Found:
558.2293.
EXAMPLE 12
[0333]
N-Butyl-4-{4-[(2S)-2-hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol--
4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonamide
[0334] The title compound was prepared from
4-((2S)-3-amino-2-hydroxy-prop-
oxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 11,
N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according to
the procedure of Example 1 as an off-white solid; mp 69-75.degree.
C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.79 (t, 3H),
1.10-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.67 (t, 2H), 2.10-3.00 (m,
5H), 3.70-4.10 (m, 5H), 6.55 (d, 3H), 6.62 (d, 1H), 6.83 (t, 1H),
7.00 (d, 2H), 7.52 (d, 2H), 10.45-10.80 (m, 2H); MS (ES) m/z :
518.1 (MH.sup.+); HRMS Calcd. for C.sub.25H.sub.36N.sub.5O.sub.5S
(MH.sup.+): 518.2437. Found: 518.2446.
EXAMPLE 13
[0335]
N-Butyl-4-{4-[(2S)-3-(9H-carbazol-4-yloxy)-2-hydroxy-propylamino]-p-
iperidin-1-yl}-benzenesulfonamide
[0336] The title compound was prepared from
1-amino-3-(9H-carbazol-4-yloxy- )-propan-2-ol and Reference Example
11, N-butyl-4-(4-oxo-piperidin-1-yl)-b- enzenesulfonamide,
according to the procedure of Example 1 as an off-white solid; mp
166-179.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
0.79 (t, 3H), 1.15-1.40 (m, 6H), 1.75-1.90 (m, 2H), 2.64 (t, 2H),
2.60-3.00 (m, 5H), 3.60-4.20 (m, 5H), 6.69 (d, 1H), 6.80-7.60 (m,
7H), 7.90 (s, 1H), 8.20 (d, 2H), 11.35 (s, 1H); MS (ES) m/z: 551.1
(MH.sup.+); HRMS Calcd. for C.sub.30H.sub.39N.sub.4O.sub.4S
(MH.sup.+): 551.2692. Found: 551.2664.
EXAMPLE 14
[0337]
N-Butyl-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-ph-
enyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide
[0338] The title compound was prepared from
N-[5-((1R)-2-Amino-1-hydroxy-e-
thyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example
11, N-butyl-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, according
to the procedure of Example 1 as a white solid; mp 71-75.degree.
C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 0.80 (t, 3H), 1
.10-1.40 (m, 6H), 1.80-1.95 (m, 2H), 2.50-2.90 (m, 5H), 2.92 (s,
3H), 3.70-3.90 (m, 2H), 4.45-4.55 (m, 1H), 6.82 (d, 1H), 7.02 (d,
3H), 7.19 (d, 1H), 7.54 (d, 2H); MS (ES) m/z : 541.0 (MH.sup.+);
HRMS Calcd. for C.sub.24H.sub.37N.sub.4O.sub.6S.sub.2 (MH.sup.+):
541.2155. Found: 541.2136.
EXAMPLE 15
[0339]
1-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethy-
lamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid isopropyl ester
[0340] The title compound was prepared from
N-[5-((1R)-2-Amino-1-hydroxy-e-
thyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example
14,
1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic
acid isopropyl ester, according to the procedure of Example 1 as an
off-white solid; mp 52-58.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.10-1.20 (m, 6H), 1.20-1.35 (m, 2H),
1.50-2.00 (m, 6H), 2.91 (s, 3H), 2.50-3.00 (m, 7H), 3.70-3.90 (m,
2H), 4.00 (m, 1H), 4.40-4.50 (m, 1H), 4.85-5.00 (m, 1H), 6.77 (d,
1H), 6.98 (d, 1H), 7.03 (d, 2H), 7.18 (d, 1H), 7.57 (d, 2H); MS
(ES) m/z: 625.1 (MH.sup.+); HRMS Calcd. for
C.sub.28H.sub.40N.sub.4O.sub.8S.sub.2 (MH.sup.+): 625.2360. Found:
625.2366.
EXAMPLE 16
[0341]
1-(4-{4-[2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-yloxy)-p-
ropylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid isopropyl ester
[0342] The title compound was prepared from
4-((2S)-3-Amino-2-hydroxy-prop-
oxy)-1,3-dihydro-benzoimidazol-2-one and Reference Example 14,
1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxylic
acid isopropyl ester, according to the procedure of Example 1 as an
off-white solid; mp 74-83.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.10-1.20 (m, 6H), 1.20-1.90 (m, 8H),
2.60-3.40 (m, 6H), 3.80-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.65 (d,
1H), 6.75 (d, 1H), 6.84 (t, 2H), 7.00 (d, 2H), 7.57 (d, 2H), 10.57
(br s, 1H), 10.70 (br s, 1H); MS (ES) m/z : 602.1 (MH.sup.+); HRMS
Calcd. for C.sub.29H.sub.40N.sub.5O.- sub.7S (MH.sup.+): 602.2634.
Found: 602.2642.
EXAMPLE 17
[0343]
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-ylo-
xy)-propylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid methylamide
[0344] Reference Example 20,
1-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-ben-
zenesulfonyl]-pyrrolidine-2-carboxylic acid methylamide, was
hydrolyzed to the corresponding ketone according to the procedure
of Reference Example 5, and then reacted with
4-((2S)-3-amino-2-hydroxy-propoxy)-1,3-dihydro-b-
enzoimidazol-2-one according to the procedure of Example 1 to give
the title compound as a tan solid; mp 36-39.degree. C.; .sup.1H NMR
(300 MHz, DMSO-d.sub.6) .delta. 1.20-2.00 (m, 8H), 2.55 (d, 3H),
2.50-3.40 (m, 6H), 3.70-4.10 (m, 6H), 4.85-4.95 (m, 1H), 6.55 (d,
1H), 6.60 (d, 1H), 6.80 (t, 2H), 7.35 (d, 2H), 7.60 (d, 2H), 7.90
(q, 1H), 10.60 (br s, 1H), 10.70 (br s, 1H); MS (ES) m/z: 573.1
(MH.sup.+); HRMS Calcd. for C.sub.27H.sub.37N.sub.6O.sub.6S
(MH.sup.+): 573.2490. Found: 573.2495.
EXAMPLE 18
[0345]
1-(4-{4-[2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-ethy-
lamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxylic
acid
[0346] The title compound was prepared from Example 15 according to
the procedure of Example 31 as gum; MS (ES) m/z: 583.1
(MH.sup.+).
EXAMPLE 19
[0347]
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-ph-
enyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid benzyl ester
[0348] The title compound was prepared from
N-[5-((1R)-2-Amino-1-hydroxy-e-
thyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example
18, {butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid benzyl ester, according to the procedure of Example 1 as a
white solid; mp 59-64.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 0.78 (t, 3H), 1.10-1.40 (m, 6H), 1.80-1.95
(m, 2H), 2.60-3.00 (m, 5H), 2.91 (s, 3H), 3.05 (t, 2H), 3.70-3.80
(m, 2H), 4.04 (s, 2H), 4.40-4.50 (m, 1H), 5.20 (s, 2H), 6.80 (d,
1H), 6.95 (d, 2H), 7.00 (d, 2H), 7.18 (d, 1H), 7.30-7.45 (m, 5H),
7.50 (d, 2H); MS (ES) m/z: 689.1 (MH.sup.+).
EXAMPLE 20
[0349]
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-ph-
enyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid
[0350] Example 19 (0.20 g, 0.29 mmol) and a catalytic amount of 10%
Pd/C in methanol (10 ml) was hydrogenated at 37 psi for 18 h. The
mixture was filtered through Celite and evaporated to give 0.10 g
of the title compound as an off-white solid; mp 125-138.degree. C.;
MS (ES) m/z: 599.3 (MH.sup.+).
EXAMPLE 21
[0351]
(2R)-1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-ph-
enyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxyli-
c acid benzyl ester
[0352] The title compound was prepared from
N-[5-((1R)-2-Amino-1-hydroxy-e-
thyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example
23,
(2R)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxyli-
c acid benzyl ester, according to the procedure of Example 1 as a
white solid; mp 62-69.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H),
2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m,
1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H),
7.40-7.50 (m, 5H), 7.52 (d, 2H); MS (ES) m/z: 673.1.1
(MH.sup.+).
EXAMPLE 22
[0353]
(2S)-1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-ph-
enyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-2-carboxyli-
c acid benzyl ester
[0354] The title compound was prepared from
N-[5-((1R)-2-Amino-1-hydroxy-e-
thyl)-2-hydroxy-phenyl]-methanesulfonamide and Reference Example
22,
(2S)-1-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-pyrrolidine-2-carboxyli-
c acid benzyl ester, according to the procedure of Example 1 as a
white solid; mp 65-71.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 1.20-1.40 (m, 2H), 1.40-1.90 (m, 6H),
2.50-3.20 (m, 5H), 3.75-3.85 (m, 2H), 4.15 (dd, 1H), 4.40-4.50 (m,
1H), 5.19 (s, 2H), 6.80 (d, 1H), 6.92 (d, 3H), 7.15 (d, 1H),
7.40-7.50 (m, 5H), 7.52 (d, 2H); MS (ES) m/z: 673.1 (MH.sup.+).
EXAMPLE 23
[0355]
[Butyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylamino-ph-
enyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid ethyl ester
[0356] The title compound was prepared according to the procedure
of Example 1 from 1.03 g (2.6 mmol) of Reference Example 43,
{butyl-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-amino}-acetic
acid ethyl ester, and 0.77 g (3.1 mmol) of
(R)-N-[5-(2-amino-1-hydroxy-ethyl)--
2-hydroxy-phenyl}-methanesulfonamide, yielding 1.05 g of a light
yellow solid; m.p. 94-95.degree. C.; MS (ES) m/z 627.2 (MH.sup.+);
HRMS (ES) Calcd. for C.sub.28H.sub.43N.sub.4O.sub.8S.sub.2
(MH.sup.+): 627.2517, Found: 627.2505.
EXAMPLE 24
[0357]
N-(2-Hydroxyethyl)-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfo-
nylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide
[0358] The title compound was prepared according to the procedure
of Example 1 from 0.12 g (0.4 mmol) of Reference Example 30,
N-(2-hydroxyethyl)-4-(4-oxo-piperidin-1-yl)-benzenesulfonamide, and
0.12 g (0.5 mmol) of
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-meth-
anesulfonamide, yielding 0.22 g of an off-white solid; m.p.
78-81.degree. C.; MS (ES) m/z 529.2 (MH.sup.+); HRMS (ES) Calcd.
for C.sub.22H.sub.33N.sub.4O.sub.7S.sub.2 (MH.sup.+): 529.1785,
Found: 529.1779.
EXAMPLE 25
[0359]
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)--
ethylamino]-piperidin-1-yl}-benzenesulfonyl)-methyl-amino]-acetic
acid ethyl ester
[0360] The title compound was prepared from Reference Example 42
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a light brown solid;
.sup.1H NMR (DMSO) .delta. 1.15 (t, J=3.3 Hz, 3H), 1.23-1.35 (m,
2H), 1.83-1.91 (m, 2H), 2.60-2.71 (m, 5H), 2.87-2.96 (m, 3H), 2.92
(s, 3H), 3.38-3.48 (m, 2H), 3.80-3.89 (m, 5H), 4.06 (q, J=3.03 Hz,
2H), 4.48-4.52 (m, 1H), 5.37 (bs, 1H), 6.83 (d, J=8.25 Hz, 1H),
6.98-7.04 (m, 3H), 7.18 (d, J=1.98 Hz, 1H), 7.52 (d, J=9.0 Hz, 2H);
MS (ES) m/z 585.2 (MH.sup.+); HRMS for
C.sub.25H.sub.36N.sub.4O.sub.8S.sub.2: 585.2034
EXAMPLE 26
[0361]
N-Cyclopropylmethyl-4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulf-
onylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonamide
[0362] The title compound was prepared from Reference Example 40
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a beige solid; .sup.1H
NMR (DMSO) .delta. 0.02-0.1 (m, 2H), 0.3-0.4 (m, 2H), 0.73-0.82 (m,
1H), 1.23-1.33 (m, 2H), 1.81-1.90 (m, 2H), 2.56 (d, J=6.81 Hz, 2H),
2.60-2.71 (m, 4H), 2.83-2.88 (m, 3H), 2.92 (s, 3H), 3.17 (s, 2H),
3.76-3.80 (m, 2H), 4.46-4.50 (m, 1H), 5.5 (bs, 1H), 6.82 (d, J=8.22
Hz, 1H), 6.98-7.02 (m, 3H), 7.18 (d, J=1.98 Hz, 1H), 7.53 (d, J=9.0
Hz, 2H); MS (ES) m/z 539.2 (MH.sup.+); HRMS for
C.sub.24H.sub.34N.sub.4O.sub.6S.sub.2: 539.1985
EXAMPLE 27
[0363]
4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-et-
hylamino]-piperidin-1-yl}-N-isobutyl-benzenesulfonamide
[0364] The title compound was prepared from Reference Example 39
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a beige solid; .sup.1H
NMR (DMSO) .delta. 0.79 (d, J=6.66 Hz, 6H), 1.23-1.35 (m, 2H),
1.53-1.67 (m, 1H), 1.82-1.90 (m, 2H), 2.45 (d, J=6.81 Hz, 2H),
2.59-2.72 (m, 4H), 2.84-2.88 (m, 3H), 2.92 (s, 3H), 3.17 (s, 2H),
3.77-3.81 (m, 2H), 4.47-4.51 (m, 1H), 5.4 (bs, 1H), 6.82 (d, J=8.25
Hz, 1H), 6.99-7.03 (m, 3H), 7.18 (d, J=2.01 Hz, 1H), 7.53 (d, J=9.0
Hz, 2H); MS (ES) m/z 541.3 (MH.sup.+); HRMS for
C.sub.24H.sub.36N.sub.4O.sub.6S.sub.2: 541.2138
EXAMPLE 28
[0365]
[Cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulf-
onylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acet-
ic acid ethyl ester
[0366] The title compound was prepared from Reference Example 45
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a tan solid; .sup.1H NMR
(DMSO) .delta. 0.76-0.83 (m, 2H), 1.14 (t, J=7.11 Hz, 3H),
1.23-1.33 (m, 2H), 1.82-1.90 (m, 2H), 2.58-2.71 (m, 5H), 2.86-2.97
(m, 4H), 2.92 (s, 3H), 2.98 (d, J=6.9 Hz, 2H), 3.16 (s, 2H),
3.78-3.83 (m, 2H), 4.00-4.07 (m, 4H), 4.46-4.51 (m, 1H), 5.3 (bs,
1H), 6.82 (d, J=8.22 Hz, 1H), 6.97-7.03 (m, 3H), 7.18 (d, J=1.98
Hz, 1H), 7.54 (d, J=9.03 Hz, 2H); MS (ES) m/z 625.3 (MH.sup.+);
HRMS for C.sub.28H.sub.40N.sub.4O.sub.8S.sub.2- : 625.2350
EXAMPLE 29
[0367]
4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-et-
hylamino]-piperidin-1-yl}-N-isopropyl-benzenesulfonamide
[0368] The title compound was prepared from Reference Example 44
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as an off-white solid;
.sup.1H NMR (DMSO) .delta. 0.92 (d, J=6.57 Hz, 6H), 1.28-1.32 (m,
2H), 1.76-1.90 (m, 2H), 2.58-2.68 (m, 5H), 2.83-2.88 (m, 3H), 2.92
(s, 3H), 3.13-3.17 (m, 2H), 3.76-3.80 (m, 2H), 4.47-4.51 (m, 1H),
5.2 (bs, 1H), 6.82 (d, J=8.22 Hz, 1H), 6.99-7.03 (m, 3H), 7.18 (d,
J=1.98 Hz, 1H), 7.54 (d, J=8.97 Hz, 2H); MS (ES) m/z 527.2
(MH.sup.+); HRMS for C.sub.23H.sub.34N.sub.4O.sub.6S.sub.2:
527.1987
EXAMPLE 30
[0369]
1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-
-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-(2R)-2-carboxyli-
c acid ethyl ester
[0370] The title compound was prepared from Reference Example 53
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a light brown solid;
.sup.1H NMR (DMSO) .delta. 1.18 (t, J=7.11 Hz, 3H), 1.27-1.32 (m,
2H), 1.55-1.60 (m, 2H), 1.74-1.92 (m, 6H), 2.63-2.75 (m, 2H),
2.87-2.96 (m, 3H), 2.92 (s, 3H), 3.07-3.17 (m, 2H), 3.80-3.84 (m,
2H), 4.03-4.13 (m, 4H), 4.48 (m, 1H), 5.2 (bs, 1H), 6.82 (d, J=8.22
Hz, 1H), 6.99-7.05 (m, 3H), 7.18 (d, J=1.98 Hz, 1H), 7.56 (d,
J=9.03 Hz, 2H); MS (ES) m/z 611.1 (MH.sup.+); HRMS for
C.sub.28H.sub.40N.sub.4O.sub.8S.sub.2: 611.2195
EXAMPLE 31
[0371]
[Cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulf-
onylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acet-
ic acid
[0372] To a stirred solution of 0.15 g (.24 mmol) of
[cyclopropylmethyl-(4-{4-[(2R)-2-hydroxy-2-(4-hydroxy-3-methanesulfonylam-
ino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-amino]-acetic
acid ethyl ester () in 2 mL of ethanol, 0.1 g (2.4 mmol) of lithium
hydroxide monohydrate in 2 ml of water was added dropwise over 10
minutes. After 20 minutes, the reaction mixture was quenched with
0.13 ml (2.4 mmol) of glacial acetic acid. The solvent was removed
in vacuo and the pink aqueous residue was pipetted out of the
flask. The solid was then washed with water and ethyl acetate and
then dried via vacuum line to give 0.134 g of the title compound as
a tan solid; .sup.1H NMR (DMSO) .delta. 0.82 (m, 1H), 1.41 (m, 2H),
1.85-1.97 (m, 2H), 2.68-2.82 (m, 8H), 2.92 (s, 3H), 3.04 (d, J=6.84
Hz, 2H), 3.30 (m, 5H), 3.76 (m, 4H), 4.58 (m, 1H), 6.83 (d, J=8.25
Hz, 1H), 6.94-7.05 (m, 3H), 7.18 (d, J=1.86 Hz, 1H), 7.60 (d,
J=8.88 Hz, 2H); MS (ES) m/z 597.1 (MH.sup.+); HRMS (MH.sup.-) for
C.sub.26H.sub.36N.sub.4O.sub.8S.sub.2: 595.1904
EXAMPLE 32
[0373]
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)--
ethylamino]-piperidin-1-yl}-benzenesulfonyl)-isobutyl-amino]-acetic
acid ethyl ester
[0374] The title compound was prepared from Reference Example 46
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a light brown solid;
.sup.1H NMR (DMSO) .delta. 0.82 (d, J=6.54 Hz, 6H), 1.13 (t, J=7.11
Hz, 4H), 1.23-1.33 (m, 2H), 1.68-1.90 (m, 4H), 2.58-2.75 (m, 2H),
2.84-2.87 (m, 3H), 2.92 (s, 3H), 3.79-3.83 (m, 4H), 3.89 (s, 2H),
4.00 (q, J=7.05 Hz, 2H), 4.46-4.51 (m, 2H), 5.2 (bs, 1H), 6.82 (d,
J=8.22 Hz, 1H), 6.98-7.03 (m, 3H), 7.18 (d, J=2.01 Hz, 1H), 7.52
(d, J=9.0 Hz, 2H); MS (ES) m/z 627.2 (MH.sup.+); HRMS for
C.sub.28H.sub.42N.sub.4O.sub.8S.sub.2: 627.2509
EXAMPLE 33
[0375]
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)--
ethylamino]-piperidin-1-yl}-benzenesulfonyl)-methyl-amino]-acetic
acid
[0376] The title compound was prepared from
[(4-{4-[(2R)-2-Hydroxy-2-(4-hy-
droxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesu-
lfonyl)-methyl-amino]-acetic acid ethyl ester according to the
procedure of Example 31 as a brown solid; .sup.1H NMR (DMSO)
.delta. 1.06 (t, J=7.11 Hz, 4H), 1.43-1.47 (m, 2H), 1.90-1.95 (m,
3H), 2.64 (s, 3H), 2.72-2.87 (m, 4H), 2.92 (s, 3H), 3.41-3.47 (m,
4H), 3.84-3.88 (m, 4H), 4.64-4.66 (m, 1H), 6.85 (d, J=8.25 Hz, 1H),
6.99-7.06 (m, 3H), 7.21 (d, J=1.89 Hz, 1H), 7.52 (d, J=8.88 Hz,
2H); MS (ES) m/z 557.2 (MH.sup.+); HRMS (MH.sup.-) for
C.sub.23H.sub.32N.sub.4O.sub.8S.sub.2: 555.1580
EXAMPLE 34
[0377]
[(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)--
ethylamino]-piperidin-1-yl}-benzenesulfonyl)-isobutyl-amino]-acetic
acid
[0378] The title compound was prepared from
[(4-{4-[(2R)-2-Hydroxy-2-(4-hy-
droxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenesu-
lfonyl)-isobutyl-amino]-acetic acid ethyl ester according to the
procedure of Example 31 as an off white solid; .sup.1H NMR (DMSO)
.delta. 0.81 (d, J=6.6 Hz, 6H), 1.37-1.41 (m, 2H), 1.75-1.91 (m,
4H), 2.69-2.85 (m, 8H), 2.92 (s, 3H), 3.45 (m, 3H), 3.73 (m, 4H),
4.60-4.62 (m, 1H), 6.83 (d, J=8.25 Hz, 1H), 6.95-7.05 (m, 3H), 7.19
(d, J=2.01 Hz, 1H), 7.57 (d, J=8.94 Hz, 2H); MS (ES) m/z 597.2
(MH.sup.-); HRMS for C.sub.26H.sub.38N.sub.4O.sub.8S.sub.2:
597.2052
EXAMPLE 35
[0379]
1-(4-{4-[(2R)-2-Hydroxy-2-(4-hydroxy-3-methanesulfonylamino-phenyl)-
-ethylamino]-piperidin-1-yl}-benzenesulfonyl)-pyrrolidine-(2R)-2-carboxyli-
c acid
[0380] The title compound was prepared from
1-(4-{4-[(2R)-2-Hydroxy-2-(4-h-
ydroxy-3-methanesulfonylamino-phenyl)-ethylamino]-piperidin-1-yl}-benzenes-
ulfonyl)-pyrrolidine-(2R)-2-carboxylic acid ethyl ester according
to the procedure of Example 31 as a tan solid; .sup.1H NMR (DMSO)
.delta. 1.32-1.36 (m, 2H), 1.51 (m, 2H), 1.77 (m, 2H), 1.90 (s,
1H), 2.63-2.78 (m, 6H), 2.92 (s, 3H), 3.12-3.15 (m, 4H), 3.27 (m,
2H), 3.79 (m, 2H), 3.93-3.98 (m, 2H), 4.52-4.56 (m, 1H), 6.83 (d,
J=8.25 Hz, 1H), 6.98-7.04 (m, 3H), 7.19 (d, J=1.92 Hz, 1H), 7.57
(d, J=8.97 Hz, 2H); MS (ES) m/z 581.1 (MH.sup.-); HRMS for
C.sub.25H.sub.34N.sub.4O.sub.8S.sub.2: 581.1747
EXAMPLE 36
[0381]
ethyl(2S)-1-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl-
)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-2-pyrrolidinecar-
boxylate
[0382] The title compound was prepared from Reference Example 56
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a tan foam; .sup.1H NMR
(DMSO) .delta. 1.16 (t, J=7.08 Hz, 3H), 1.24-1.32 (m, 2H),
1.55-1.60 (m, 2H), 1.77-1.94 (m, 5H), 2.63-2.75 (m, 3H), 2.87-2.96
(m, 2H), 2.92 (s, 3H), 3.09-3.13 (m, 1H), 3.28-3.39 (m, 3H),
3.80-3.85 (m, 2H), 4.03-4.14 (m, 4H), 4.47-4.52 (m, 1H), 6.83 (d,
J=8.25 Hz, 1H), 6.99-7.05 (m, 3H), 7.18 (d, J=2.01 Hz, 1H), 7.56
(d, J=9.0 Hz, 2H); MS (ES) m/z 611.1 (MH.sup.+); HRMS for
C.sub.27H.sub.38N.sub.4O.sub.8S.sub.2: 611.2194
EXAMPLE 37
[0383]
ethyl(2S)-2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3[(methylsulfonyl-
)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}-4-methylp-
entanoate
[0384] The title compound was prepared from Reference Example 61
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a tan foam; .sup.1H NMR
(DMSO) .delta. 0.70 (d, J=6.51 Hz, 3H), 0.80 (d, J=6.6 Hz, 3H),
1.02 (t, J=7.08 Hz, 3H), 1.23-1.40 (m, 5H), 1.51-1.70 (m, 2H),
1.85-1.90 (m, 3H), 2.59-2.76 (m, 3H), 2.84-2.89 (m, 2H), 2.92 (s,
3H), 3.63 (m, 2H), 3.77-3.85 (m, 4H), 4.47-4.52 (m, 1H), 5.25 (bs,
1H), 6.82 (d, J=8.22 Hz, 1H), 6.99-7.03 (m, 3H), 7.18 (d, J=2.01
Hz, 1H), 7.48 (d, J=9.0 Hz, 2H); MS (ES) m/z 627.2 (MH.sup.+); HRMS
for C.sub.28H.sub.42N.sub.4O.sub.8S.su- b.2: 627.2509
EXAMPLE 38
[0385]
ethyl(2S)-2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfony-
l)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}-3-methyl-
butanoate
[0386] The title compound was prepared from Reference Example 62
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a brown foam; .sup.1H
NMR (DMSO) .delta. 0.80 (t, J=6.96 Hz, 3H), 1.00 (t, J=7.14 Hz,
3H), 1.23-1.34 (m, 2H), 1.76-1.90 (m, 4H), 2.60-2.72 (m, 4H),
2.83-2.88 (m, 2H), 2.92 (s, 3H), 3.39-3.41 (m, 2H), 3.74-3.83 (m,
5H), 4.48-4.52 (m, 1H), 5.3 (bs, 1H), 6.82 (d, J=8.25 Hz, 1H),
6.95-7.03 (m, 3H), 7.18 (d, J=2.01 Hz, 1H), 7.49 (d, J=9.0 Hz, 2H);
MS (ES) m/z 613.2 (MH.sup.+); HRMS for
C.sub.27H.sub.40N.sub.4O.sub.8S.sub.2: 613.2350
EXAMPLE 39
[0387]
(2S)-1-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amin-
o]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-2-pyrrolidinecarboxy-
lic acid
[0388] The title compound was prepared from
ethyl(2S)-1-[(4-{4-[((2R)-2-hy-
droxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidi-
nyl}phenyl) sulfonyl]-2-pyrrolidinecarboxylate according to the
procedure of Example 31 as a brown solid; .sup.1H NMR (DMSO)
.delta. 1.37 (m, 2H), 1.46-1.50 (m, 1H), 1.68-1.79 (m, 3H),
1.85-1.96 (m, 2H), 1.90 (s, 1H), 2.65-2.72 (m, 3H), 2.77-2.89 (m,
3H), 2.92 (s, 3H), 3.06-3.12 (m, 2H), 3.21-3.23 (m, 3H), 3.80-3.85
(m, 2H), 3.92-3.96 (m, 1H), 4.56-4.58 (m, 1H), 6.84 (d, J=8.28 Hz,
1H), 6.99-7.05 (m, 3H), 7.20 (d, J=1.95 Hz, 1H), 7.57 (d, J=8.97
Hz, 2H); MS (ES) m/z 583.1 (MH.sup.+); HRMS for
C.sub.25H.sub.34N.sub.4O.sub.8S.sub.2: 583.1883
EXAMPLE 40
[0389] ethyl
1-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-nyl}phenyl)sulfonyl-
]amino}-cyclopentanecarboxylate
[0390] The title compound was prepared from Reference Example 66
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a beige solid; .sup.1H
NMR (DMSO) .delta. 1.11 (t, J=7.11 Hz, 3H), 1.27-1.30 (m, 4H), 1.49
(m, 4H), 1.88 (m, 8H), 2.63-2.73 (m, 3H), 2.83-2.88 (m, 2H), 2.92
(s, 3H), 3.77-3.82 (m, 2H), 3.89 (q, J=708 Hz, 2H), 4.48 (m, 1H),
5.2 (bs, 1H), 6.82 (d, J=8.25 Hz, 1H), 6.95-7.03 (m, 3H), 7.18 (d,
J=2.01 Hz, 1H), 7.50 (d, J=9.0 Hz, 2H); MS (ES) m/z 625.2
(MH.sup.+); HRMS for C.sub.28H.sub.40N.sub.4O.sub.8S.sub.2:
625.2361
EXAMPLE 41
[0391]
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-({1-[4-(1-pyrrolidinylsulfonyl)phe-
nyl]-piperidinyl}-4-amino)ethyl]phenyl}methanesulfonamide
[0392] The title compound was prepared from Reference Example 34
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a beige solid; .sup.1H
NMR (DMSO) .delta. 1.23-1.35 (m, 2H), 1.60-1.65 (m, 4H), 1.83-1.91
(m, 2H), 2.59-2.76 (m, 5H), 2.86-2.95 (m, 2H), 2.92 (s, 3H),
3.03-3.08 (m, 4H), 3.16 (s, 1H), 3.79-3.84 (m, 2H), 4.47-4.52 (m,
1H), 5.3 (bs, 1H), 6.82 (d, J=8.25 Hz, 1H), 6.99-7.05 (m, 3H), 7.18
(d, J=2.01 Hz, 1H), 7.54 (d, J=8.97 Hz, 2H); MS (ES) m/z 539.2
(MH.sup.+); HRMS for C.sub.24H.sub.34N.sub.4O.sub.6S.sub.2:
539.1990
EXAMPLE 42
[0393]
N-{2-hydroxy-5-[(1R)-1-hydroxy-2-({1-[4-(1-piperidinylsulfonyl)phen-
yl]-piperidinyl}-4-amino)ethyl]phenyl}methanesulfonamide
[0394] The title compound was prepared from Reference Example 35
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as an off white solid;
.sup.1H NMR (DMSO) .delta. 1.24-1.35 (m, 4H), 1.50-1.53 (m, 4H),
1.83-1.90 (m, 2H), 2.59-2.71 (m, 4H), 2.75-2.82 (m, 4H), 2.87-2.95
(m, 2H), 2.92 (s, 3H), 3.17 (s, 2H), 3.79-3.84 (m, 2H), 4.47-4.51
(m, 1H), 5.3 (bs, 1H), 6.82 (d, J=8.25 Hz, 1H), 6.99-7.05 (m, 3H),
7.18 (d, J=2.01 Hz, 1H), 7.46 (d, J=9.0 Hz, 2H); MS (ES) m/z 553.2
(MH.sup.+); HRMS for C.sub.25H.sub.36N.sub.4O.sub.6S.sub.2:
553.2149
EXAMPLE 43
[0395] Ethyl
1-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-inyl}phenyl)sulfony-
l]amino}-cyclohexanecarboxylate
[0396] The title compound was prepared from Reference Example 68
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a beige solid; .sup.1H
NMR (DMSO) .delta. 1.10 (t, J=7.14 Hz, 3H), 1.23-1.33 (m, 8H),
1.63-1.90 (m, 6H), 2.59-2.76 (m, 4H), 2.83-2.88 (m, 2H), 3.17 (s,
3H), 3.77-3.86 (m, 2H), 4.47-4.52 (m, 1H), 5.3 (bs, 1H), 6.82 (d,
J=8.22 Hz, 1H), 6.96-7.03 (m, 3H), 7.18 (d, J=1.98 Hz, 1H), 7.51
(d, J=8.97 Hz, 2H); MS (ES) m/z 639.2 (MH.sup.+); HRMS for
C.sub.29H.sub.42N.sub.4O.sub.8S.sub.2: 639.2517
EXAMPLE 44
[0397] Ethyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-idinyl}phenyl)sulfony-
l]-(isopropyl)amino]acetate
[0398] The title compound was prepared from Reference Example 69
and
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide
according to the procedure of Example 1 as a beige solid; .sup.1H
NMR (DMSO) .delta. 0.91 (d, J=6.69 Hz, 6H), 1.19 (t, J=7.08 Hz,
3H), 1.28-1.35 (m, 2H), 1.83-1.90 (m, 2H), 2.59-2.76 (m, 5H), 2.86
(m, 2H), 2.92 (s, 3H), 3.74-3.84 (m, 4H), 3.91 (s, 2H), 4.10 (q,
J=7.05 Hz, 2H), 4.47-4.52 (m, 1H), 5.3 (bs, 1H), 6.82 (d, J=8.25
Hz, 1H), 6.99-7.03 (m, 3H), 7.18 (d, J=2.01 Hz, 1H), 7.62 (d,
J=9.03 Hz, 2H); MS (ES) m/z 613.2 (MH.sup.+); HRMS for
C.sub.29H.sub.42N.sub.4O.sub.8S.sub.2: 613.2362
EXAMPLE 45
[0399]
N-[2-Hydroxy-5-(1-hydroxy-2-{1-[4-(toluene-4-sulfonyl)-phenyl]-pipe-
ridin-4-ylamino}-ethyl)-phenyl]-methanesulfonamide
[0400] The title compound was prepared according to the procedure
of Example 1 from 0.13 g (0.4 mmol) of Reference Example 25,
1-[4-(Toluene-4-sulfonyl)-phenyl]-piperidin-4-one, and 0.12 g (0.5
mmol) of
(R)-N-[5-(2-amino-1-hydroxy-ethyl)-2-hydroxy-phenyl}-methanesulfonamid-
e, yielding 0.18 g of a white solid; m.p. 115-118.degree. C.; MS
(ES) m/z 560.0 (MH.sup.+); HRMS (FAB) Calcd. for
C.sub.27H.sub.34N.sub.3O.sub.6S.s- ub.2 (MH.sup.+): 560.1889,
Found: 560.1886.
EXAMPLE 46
[0401]
4-((2S)-2-Hydroxy-3-{1-[4-(toluene-4-sulfonyl)-phenyl]-piperidin-4--
ylamino}-propoxy)-1,3-dihydro-benzoimidazol-2-one
[0402] The title compound was prepared according to the procedure
of Example 1 from 0.13 g (0.4 mmol) of Reference Example 25,
1-[4-(toluene-4-sulfonyl)-phenyl]-piperidin-4-one, and 0.13 g (0.6
mmol) of
4-((2S)-3-Amino-2-hydroxy-propoxy)-1,3-dihydro-benzoimidazol-2-one,
yielding 0.18 g of a white solid; m.p. 130-132.degree. C.; MS (ES)
m/z 537.0 (MH.sup.+); HRMS (FAB) Calcd. for
C.sub.28H.sub.33N.sub.4O.sub.5S (MH.sup.+): 537.2166, Found:
537.2169.
EXAMPLE 47
[0403]
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulf-
onyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-4-hexynoica-
cid tert-butyl ester
[0404] The title compound was prepared according to the procedure
of Example 1 from 0.37 g (0.8 mmol) of Reference Example 27,
2-But-2-ynyl-2-[4-(4-oxo-piperidin-1-yl)-benzenesulfonyl]-hex-4-ynoic
acid tert-butyl ester, and 0.24 g (1.0 mmol) of
(R)-N-[5-(2-amino-1-hydro-
xy-ethyl)-2-hydroxy-phenyl}-methanesulfonamide, yielding 0.54 g of
an off-white solid; m.p. 93-95.degree. C.; MS (ES) m/z 688.2
(MH.sup.+); HRMS (ES) Calcd. for
C.sub.34H.sub.46N.sub.3O.sub.8S.sub.2 (MH.sup.+): 688.2721, Found:
688.2722.
EXAMPLE 48
[0405]
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulf-
onyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-4-hexynoica-
cid
[0406] To a solution of
2-(2-butynyl)-2-[(4-{4-[((2R)-2-hydroxy-2-{4-hydro-
xy-3-[(methylsulfonyl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulf-
onyl]-4-hexynoicacid tert-butyl ester 0.21 g (0.3 mmol) in
dichloromethane (3 ml) was added trifluoroacetic acid (0.23 ml, 3
mmol), and the mixture was stirred at room temperature for 2 days.
It was then evaporated and treated with 10% sodium bicarbonate
solution until pH 6. The resulting suspension was filtered and the
precipitate washed with water, and dried in vacuo to give 85 mg of
a beige solid; m.p. 175-177.degree. C.; MS (ES) m/z 630.6
(M-H.sup.-); HRMS (EI) Calcd. for C.sub.30H.sub.36N.sub.3O.sub.-
8S.sub.2 (M-H.sup.-): 630.1949, Found: 630.1943.
EXAMPLE 49
[0407]
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidazol-4-ylo-
xy)-propylamino]-piperidin-1-yl}-benzenesulfonyl)-imidazolidine-2,4-dione
[0408] Step a) N-[(4-fluorophenyl)sulfonyl]-glycine
[0409] A saturated sodium carbonate solution was added dropwise
into a mixture of 4-fluorobenzenesulfonyl chloride (30.0 g, 154
mmol), glycine (11.5 g, 154 mmol), and dioxane (200 mL), until a
basic (pH about 9) solution was achieved. After 30 minutes the
mixture was neutralized with HCl (2 N), and the volatiles were
removed in vacuo. The residue was recrystallized from cold
(0.degree. C.) to yield a white solid (23.6 g, 66% yield): mp
144-146.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
3.58 (s, 2H), 7.39-7.42 (m, 2H), 7.81-7.86 (m, 2H), 8.06 (brs, 1H),
12.5 (brs, 1H); MS m/e 232 (M-H).sup.+;
[0410] Analysis for: C.sub.8H.sub.8FNO.sub.4S Calc'd: C, 41.20; H,
3.46; N, 6.01 Found: C, 41.14; H, 3.51; N, 5.85
[0411] Step b)
1-[(4-Fluorophenyl)sulfonyl]-2-thioxo-4-imidazolidinone
[0412] A mixture of N-[(4-fluorophenyl)sulfonyl]-glycine (17.0 g,
72.9 mmol), ammonium thiocyanate (7.2 g, 94.8 mmol), acetic
anhydride (17.2 mL, 182.2 mmol), and pyridine (70 mL) was stirred
at 100.degree. C. for 24 hours. Then, the mixture was into water
and extracted with ethyl acetate. The organic extracts were dried
over MgSO4. Evaporation and purification by flash chromatography
(hexanes/ethyl acetate 2/1) gave a yellow solid (19.6 g, 98%
yield): mp 208-210.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 4.78 (s, 2H), 7.47-7.51 (m, 2H), 8.14-8.18 (m, 2H), 12.6
(s, 1H); MS m/e 274 M.sup.+;
[0413] Analysis for: C.sub.9H.sub.7FN.sub.2O.sub.3S.sub.2 Calc'd:
C, 39.41; H, 2.57; N, 10.21 Found: C, 39.90; H, 2.71; N, 10.09
[0414] Step c)
1-[(4-Fluorophenyl)sulfonyl]-2,4-imidazolidinedione
[0415] A mixture of
1-[(4-fluorophenyl)sulfonyl]-2-thioxo-4-imidazolidinon- e (14.5 g,
52.9 mmol), and chloroacetic acid (100 g) was stirred at
120.degree. C. for 2 days. Then, the mixture was poured into water
and extracted with ethyl acetate. The organic extracts were dried
over MgSO.sub.4. Evaporation and purification by flash
chromatography (hexanes/ethyl acetate 1/1) gave a white solid (12.6
g, 92% yield): mp 232-234.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 4.48 (s, 2H), 7.47-7.52 (m, 2H), 8.06-8.09
(m, 2H), 11.61 (s, 1H); MS m/e 257 (M-H).sup.+;
[0416] Analysis for: C.sub.9H.sub.7FN.sub.2O.sub.4S Calc'd: C,
41.86; H, 2.73; N, 10.85 Found: C, 42.24; H, 2.72; N, 10.6
[0417] Step d)
1-[[4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]sulfonyl]-2-
,4-imidazolidinedione
[0418] A mixture of
1-[(4-fluorophenyl)sulfonyl]-2,4-imidazolidinedione (3.6 g, 13.9
mmol), 1,4-dioxa-8-azaspiro[4.5]-decane (3.56 mL, 27.8 mmol),
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (30 mL),
acetonitrile (15 mL), and potassium carbonate (3.84 g, 27.8 mmol)
was stirred at 65.degree. C. for 2 days. Then, the mixture was
poured into water and extracted with ethyl acetate. The organic
extracts were dried over MgSO.sub.4.
[0419] Evaporation and purification by flash chromatography
(hexanes/ethyl acetate 1/1) gave a white solid (4.15 g, 78% yield):
mp 222-224.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
1.63-1.66 (m, 4H), 3.47-3.9 (m, 4H), 3.9 (s, 4H), 4.41 (s, 2H),
7.03-7.07 (m, 2H), 7.71-7.74 (m, 2H), 11.46 (brs, 1H); MS m/e 382
(M+H).sup.+;
[0420] Analysis for: C.sub.16H.sub.19N.sub.3O.sub.6S Calc'd: C,
50.39; H, 5.02; N, 11.02 Found: C, 50.22; H, 4.92; N, 10.89
[0421] Step e)
1-[[4-(4-Oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidi-
nedione
[0422] A mixture of
1-[[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]sulfon-
yl]-2,4-imidazolidinedione (4.1 g, 10.76 mmol), HCl (concentrated,
10 mL), and dioxane (15 mL) was stirred at room temperature for 5
days. Then, the mixture was poured into water and extracted with
ethyl acetate. The organic extracts were dried over MgSO.sub.4.
[0423] Evaporation and purification by flash chromatography
(hexanes/ethyl acetate 1/1) gave a white solid (3.2 g, 88% yield):
mp 210-212.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
2.48 (m, 2H), 3.78 (m, 4H), 4.44 (s, 2H), 7.06-7.08 (m, 2H),
7.76-7.79 (m, 2H), 11.48 (s, 1H); MS m/e 338 (M+H).sup.+;
[0424] Analysis for: C.sub.14H.sub.15N.sub.3O.sub.5S Calc'd: C,
49.85; H, 4.48; N, 12.46 Found: C, 49.51; H, 4.51; N, 11.84
[0425] Step f)
1-(4-{4-[(2S)-2-Hydroxy-3-(2-oxo-2,3-dihydro-1H-benzoimidaz-
ol-4-yloxy)-propylamino]-piperidin-1-yl}-benzenesulfonyl)-imidazolidine-2,-
4-dione
[0426] Acetic acid (0.14 mL, 2.38 mmol) was added dropwise into a
mixture of
4-{[(2S)-3-amino-2-hydroxypropyl]oxy}-1,3-dihydro-2H-benzimidazol-2-on-
e (265 mg, 1.19 mmol),
1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imi-
dazolidinedione (400 mg, 1.19 mmol) and N,N-dimethylformamide (5
mL). The mixture was stirred for 20 minutes and then, sodium
triacetoxyborohydride (303 mg, 1.43 mmol) was added, and the new
mixture was stirred at room temperature for 24 hours. The volatiles
were removed in vacuo and the residue was purified by flash
chromatography (dichloromethane/methyl alcohol 3/1) to produce a
brown solid (256 mg, 40% yield): mp 230.degree. C. (decomposed); 'H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.52-1.63 (m, 2H), 2.04-2.15
(m, 2H), 2.48 (m, 2H), 2.9-3.0 (m, 2H), 3.13-3.15 (m, 1H), 3.2-3.4
(m, 3H), 4.0-4.1 (m, 5H), 4.42 (s, 2H), 6.6-6.63 (m, 2H), 6.8-6.85
(m, 1H), 7.03-7.05 (m, 2H), 7.78-7.8 (m, 2H), 10.6 (s, 1H), 10.7
(s, 1H); MS m/e 543 (M-H).sup.+;
[0427] Analysis for: C.sub.24H.sub.28N.sub.6O.sub.7S Calc'd: C,
45.24; H, 5.38; N, 12.88 Found: C, 45.88; H, 5.36; N, 13.88
EXAMPLE 50
[0428]
N-[5-((1R)-2-{1-[4-(2,4-Dioxo-imidazolidine-l-sulfonyl)-phenyl]pipe-
ridin-4-ylamino}-1-hydroxy-ethyl)-2-hydroxy-phenyl]-methanesulfonamide
[0429] Acetic acid (0.15 mL, 2.6 mmol) was added dropwise into a
mixture
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
(320 mg, 1.3 mmol),
1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imida-
zolidinedione (440 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL).
The mixture was stirred for 20 minutes and then, sodium
triacetoxyborohydride (331 mg, 1.56 mmol) was added, and the new
mixture was stirred at room temperature for 24 hours. The volatiles
were removed in vacuo and the residue was purified by flash
chromatography (dichloromethane/methyl alcohol 4/1) to produce a
white solid (496 mg, 67% yield): mp 200-202.degree. C.; .sup.C
1.35-1.42 (m, 2H), 1.81-1.97 (m, 2H), 2.7-2.82 (m, 2H), 2.83-2.97
(m, 6H), 3.95-3.97 (m, 2H), 4.22 (s, 2H), 4.57-4.6 (m, 1H), 6.82
(m, 1H), 7.1 (m, 3H), 7.2 (m, 1H), 7.75 (m, 2H), 8.4 (brs, 2H); MS
m/e 566 (M-H).sup.+;
[0430] Analysis for: C.sub.23H.sub.29N.sub.5O.sub.8S.sub.2 Calc'd:
C, 48.67; H. 5.11; N. 12.34 Found: C, 47.64; H, 5.2; N, 11.26
EXAMPLE 51
[0431]
1-(4-{4-[((2S)-2-Hydroxy-2-(2-trifluoromethyl-thiazol-4-yl)-ethylam-
ino]-piperidin-1-yl}-benzenesulfonyl)-imidazolidine-2,4-dione
[0432] Acetic acid (0.09 mL, 1.6 mmol) was added dropwise into a
(1S)-2-amino-1-[2-(trifluoromethyl)-1,3-thiazol-4-yl]-1-ethanol
(152 mg, 0.71 mmol),
1-[[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl]-2,4-imidazolidine-
dione (220 mg, 0.65 mmol) and N,N-dimethylformamide (3 mL). The
mixture was stirred for 20 minutes and then, sodium
triacetoxyborohydride (276 mg, 1.3 mmol) was added, and the new
mixture was stirred at room temperature for 24 hours. The volatiles
were removed in vacuo and the residue was purified by flash
chromatography (dichloromethane/methyl alcohol 4/1) to produce an
off-white solid (265 mg, 68% yield): mp 185-187.degree. C.; .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.22-1.35 (m, 2H), 1.8-1.9 (m,
1H), 2.7-2.83 (m, 2H), 2.9-3.01 (m, 3H), 3.8 (m, 2H), 4.2 (s, 2H),
4.81 (m, 1H), 7.1 (m, 2H), 7.8 (m, 2H), 7.95 (s, 1H); MS m/e 534
(M+H).sup.+;
[0433] Analysis for: C.sub.20H.sub.22F.sub.3N.sub.5O.sub.5S.sub.2
Calc'd: C, 45.02; H, 4.16; N, 13.13 Found: C, 42.79; H, 4.27; N,
11.95
EXAMPLE 52
[0434] tert-Butyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfon-
yl)amino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate
[0435] Step a) tert-Butyl
2-{[(4-fluorophenyl)sulfonyl]amino}acetate
[0436] N,N-Diisopropylethylamine (41.4 mL, 238.8 mmol) was added
into a mixture of 4-fluorobenzenesulfonyl chloride (23.2 g, 119.4
mmol), glycine tert-butyl ester hydrochloride (20 g, 119.4 mmol)
and tetrahydrofuran (200 mL). The mixture was stirred for 24 hours.
The volatiles were then removed in vacuo, and the residue was taken
in water (2000 mL) and stirred for 30 minutes. The precipitated
solid was filtered and dried to give a white solid (32.1 g, 93%
yield): mp 105-107.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.28 (s, 9H), 3.6 (7.4 (m, 2H), 7.83 (m, 2H), 8.17 (t,
J=6.37 Hz, 1H); d, J=6.37 Hz, 2H), MS m/e 289 M.sup.+;
[0437] Analysis for: C.sub.12H.sub.16FNO.sub.4S Calc'd: C, 49.82;
H, 5.57; N, 4.84 Found: C, 50.06; H, 5.72; N, 4.79
[0438] step b) tert-Butyl
2-({[4-(4-hydroxy-1-piperidinyl)phenyl]sulfonyl}- amino)acetate
[0439] A mixture of tert-butyl
2-{[(4-fluorophenyl)sulfonyl]amino}acetate (22.5 g, 77.8 mmol),
4-hydroxypiperidine (11.8 g, 116.8 mmol), potassium carbonate (16.1
g, 116.8 mmol), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyr-
imidinone (90 mL), and acetonitrile (60 mL) was stirred at
75.degree. C. for 2 days. The mixture was poured into water and
extracted with ethyl acetate. The organic extracts were dried over
MgSO.sub.4. Evaporation and purification by flash chromatography
(hexanes/ethyl acetate 1/1) gave a white solid (22.1 g, 77 %
yield): mp 125-127.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.29 (s, 9H), 1.4 (m, 2H), 2.79 (m, 2H), 3.0 (m, 2H), 3.46
(m, 2H), 3.68 (m, 3H), 4.72 (m, 1H), 7.0 (m, 2H), 7.56 (m, 2H),
7.68 (m, 1H); MS m/e 371 (M+H).sup.+;
[0440] Analysis for: C.sub.17H.sub.26N.sub.2O.sub.5S Calc'd: C,
55.12; H, 7.07; N, 7.56 Found: C, 55.45; H, 7.24; N, 7.52
[0441] Step c) tert-Butyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amin- o)acetate
[0442] Trifluoroacetic acid (0.21 mL, 2.7 mmol) was added dropwise
into a cold (0.degree. C.) mixture of tert-butyl
2-({[4-(4-hydroxy-1-piperidinyl- )phenyl]sulfonyl}amino)acetate
(2.0 g, 5.4 mmol), dimethyl sulfoxide (15 mL), benzene (15 mL),
pyridine (0.43 mL, 5.44 mmol), and 1,3-dicyclohexylcarbodiimide
(3.34 g, 16.2 mmol). The mixture was allowed to come to room
temperature, stirred for 20 hours, and then diluted with ethyl
acetate. The precipitated solid was filtered and discarded. The
filtrate was washed with water, and dried over MgSO.sub.4.
Evaporation and purification by flash chromatography (hexanes/ethyl
acetate 1/1) gave a white solid (1.85 g, 93% yield): mp
130-132.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
1.29 (s, 9H), 2.4 (m, 4H), 3.46 (d, J=6.15 Hz, 2H), 3.73 (m, 4H),
7.07 (m, 2H), 7.58 (m, 2H), 7.69 (t, J=6.15 Hz, 1H); MS m/e 368
M.sup.+;
[0443] Analysis for: C.sub.17H.sub.26N.sub.2O.sub.5S Calc'd: C,
55.42; H, 6.57; N, 7.60 Found: C, 55.56; H, 6.41; N, 7.57
[0444] Step d) tert-Butyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(meth-
ylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}a-
cetate
[0445] Acetic acid (2.92 mL, 5.1 mmol) was added dropwise into a
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
(627 mg, 2.55 mmol), tert-butyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfon- yl}amino)acetate (940
mg, 2.55 mmol), and N,N-dimethylformamide (7 mL). The mixture was
stirred for 20 minutes and then, sodium triacetoxyborohydride (649
mg, 3.06 mmol) was added, and the new mixture was stirred at room
temperature for 24 hours. The volatiles were removed in vacuo and
the residue was purified by flash chromatography
(dichloromethane/methyl alcohol 8/1) to produce a white solid (1.21
g, 80% yield): mp 113-115.degree. C.; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.23-1.29 (m, 11H), 1.8-1.83 {m, 2H),
2.6-2.7 (m, 3H), 2.81-28.3 (m, 2H), 2.91 (s, 3H), 3.45 (s, 2H),
3.79 (m, 2H), 4.47 (m, 1H), 6.95 (m, 1H), 7.0 (m, 3H), 7.18 (m,
1H), 7.5 (m, 2H); MS m/e 599 (M+H).sup.+;
[0446] Analysis for:
C.sub.26H.sub.38N.sub.4O.sub.8S.sub.2.times.1CH.sub.3- CO.sub.2H
Calc'd: C, 51.05; H, 6.43; N, 8.50 Found: C, 51.08; H, 6.49; N,
8.70
EXAMPLE 53
[0447]
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]ph-
enyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetic
acid
[0448] A mixture of tert-butyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[-
(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]-a-
mino}acetate (600 mg, 1 mmol), dichloromethane (10 mL), and
trifluoroacetic acid (2 mL) was stirred at room temperature for 15
hours. The mixture was then poured into ethyl ether (50 mL) and the
precipitated solid was filtered and dried. Purified by HLPC reverse
phase chromatography (YMC C18 column, 85:15 water:0.1%
trifluoroacetic acid/acetonitrile) to yield a white solid (340 mg,
51%): mp 170-172.degree. C.; MS m/e 541 (M-H).sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.4-1.5 (m, 2H), 1.9-2.0 (m, 2H),
2.75-3.1 (m, 8H), 3.2 (s, 2H), 3.84 (m, 2H), 4.65 (m, 1H), 6.83 (m,
2H), 7.0-7.06 (m, 3H), 7.2 (m, 1H), 7.6 (2H);
[0449] Analysis for:
C.sub.22H.sub.30N.sub.4O.sub.8S.sub.2.times.0.5 CF.sub.3CO.sub.2H
Calc'd: C, 46.08; H, 5.09; N, 9.35 Found: C, 46.15; H, 4.99; N,
9.13
EXAMPLE 54
[0450] tert-Butyl
2-{[2-(tert-butoxy)-2-oxoethyl][(4-{4-[((2R)-2-hydroxy-2-
-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}-ph-
enyl)sulfonyl]amino}acetate
[0451] Step a) tert-Butyl
2-([2-(tert-butoxy)-2-oxoethyl]{[4-(4-oxo-1-pipe-
ridinyl)phenyl]sulfonyl}amino)acetate
[0452] Sodium hydride (60% in mineral oil, 109 mg, 2.72 mmol) was
added into a solution of tert-butyl
2-(([4-(4-oxo-1-piperidinyl)phenyl]sulfonyl- }amino)acetate 91 g,
2.72 mmol), and N,N-dimethylformamide (5 mL). The mixture was
stirred at room temperature for 2 hours, and then tert-butyl
bromoacetate (0.48 mL, 3.26 mmol) was added dropwise. The new
mixture was stirred for 1 hour, poured into water and extracted
with ethyl acetate. The organic extracts were dried over
MgSO.sub.4. Evaporation and purification by flash chromatography
(hexanes/ethyl acetate 2/1) gave a yellow oil (670 mg, 52% yield):
MS m/e 482 (M)+; .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.31
(s, 18H), 2.4 (m, 4H), 3.75 (m, 4H), 3.95 (s, 4H), 7.05 (m, 2H),
7.58 (m, 2H); Analysis for: C.sub.23H.sub.34N.sub.2O.s- ub.7S
Calc'd: C, 57.24; H, 7.10; N, 5.80 Found: C, 57.27; H, 7.22; N,
5.84
[0453] Step b) tert-Butyl
2-{[2-(tert-butoxy)-2-oxoethyl][(4-{4-[((2R)-2-h-
ydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperid-
inyl}phenyl)sulfonyl]amino}acetate
[0454] Acetic acid (0.95 mL, 1.66 mmol) was added dropwise into a
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
(204 mg, 0.83 mmol), tert-butyl
2-([2-(tert-butoxy)-2-oxoethyl]{[4-(4-oxo- -1-piperidinyl)
phenyl]sulfonyl}amino)acetate (400 mg, 0.83 mmol), and
N,N-dimethylformamide (4 mL). The mixture was stirred for 20
minutes and then, sodium triacetoxyborohydride (211 mg, 0.99 mmol)
was added, and the new mixture was stirred at room temperature for
24 hours. The volatiles were removed in vacuo and the residue was
purified by flash chromatography (dichloromethane/methyl alcohol
8/1) to produce a white solid (520 mg, 88% yield): mp
164-166.degree. C.; MS m/e 713 (M+H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.27 (m, 2H), 1.31 (s, 18H), 1.84 (m, 2H),
1.62-1.75 (m, 3H), 2.85-2.95 (m, 5H), 38. (m, 2H), 3.93 (s, 4H),
4.5 (m, 1H), 6.8 (m, 1H), 6.98-7.01 (m 2H), 7.17 (1H), 7.51 (m,
2H);
[0455] Analysis for: C.sub.32H.sub.48N.sub.4O.sub.10S.sub.2.times.1
CH.sub.3CO.sub.2H Calc'd: C, 52.83; H, 6.78; N, 7.25 Found: C,
51.85; H, 6.61; N, 7.07
EXAMPLE 55
[0456]
2-{(Carboxymethyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsu-
lfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}aceti-
c acid
[0457] A mixture of tert-butyl
2-{[2-(tert-butoxy)-2-oxoethyl][(4-{4-[((2R-
)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-pi-
peridinyl}phenyl)sulfonyl]amino}acetate (400 mg, 0.56 mmol),
dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was
stirred at room temperature for 15 hours. The mixture was then
poured into ethyl ether (50 mL) and the precipitated solid was
filtered and dried. The crude solid was dissolved in methyl alcohol
(5 mL) and added slowly into ethyl ether (50 mL). The precipitated
solid was filtered and dried to yield a white solid (465 mg, 67%):
mp 163-166.degree. C.; MS m/e 599 (M-H).sup.+; .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 1.5-1.6 (m, 2H), 2.0-2.1 (m, 2H),
2.8-3.2 (m, 8H), 3.8 m, 2H), 4.0 (m, 2H), 4.8 (m, 1H), 6.9 (m, 1H),
7.05 (m, 3H), 7.2 (m, 1H), 7.6 (m, 2H);
[0458] Analysis for:
C.sub.24H.sub.32N.sub.4O.sub.10S.sub.2.times.0.5 CF.sub.3CO.sub.2H
Calc'd: C, 44.97; H, 4.94; N, 8.52 Found: C, 44.74; H, 4.75; N,
8.19
EXAMPLE 56
[0459] Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)am-
ino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate
[0460] Step a) Ethyl 2-{[(4-fluorophenyl)sulfonyl]amino}acetate
N,N-Diisopropylethylamine (26.8 mL, 154.2 mmol) was added into a
mixture of 4-fluorobenzenesulfonyl chloride (15 g, 77.1 mmol),
glycine ethyl ester hydrochloride (10.7 g, 77.1 mmol) and
tetrahydrofuran (200 mL). The mixture was stirred for 24 hours. The
volatiles were then removed in vacuo, and the residue was taken in
water and extracted with ethyl acetate. The organic extracts were
dried over MgSO.sub.4. Evaporation and purification by flash
chromatography (hexanes/ethyl acetate 4/1) gave a white solid (19.6
g, 93% yield): mp 90-92.degree. C.; MS m/e 260 (M-H).sup.+; .sup.1H
NMR (400 MHz, DMSO-d.sub.6): .delta. 1.05 9t, J=7.02 Hz, 3H), 3.7
9d, J=7.25 Hz, 2H), 3.98 (q, J=7.02 Hz, 2H), 7.4 (m, 2H), 7.83 (m,
2H0, 8.23 (t, J=7.25 Hz, 1H);
[0461] Analysis for: C.sub.10H.sub.12FNO.sub.4S Calc'd: C, 45.97;
H, 4.63; N, 5.36 Found: C, 46.12; H, 4.50; N, 5.37
[0462] Step b) Ethyl
2-({[4-(4-hydroxy-1-piperidinyl)phenyl]sulfonyl}amino- )acetate
[0463] A mixture of ethyl
2-{[(4-fluorophenyl)sulfonyl]amino}acetate (25 g, 95.8 mmol),
4-hydroxypiperidine (14.5 g, 143.7 mmol), potassium carbonate (19.8
g, 143.7 mmol), 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1-pyrimidinone
(90 mL), and acetonitrile (60 mL) was stirred at 75.degree. C. for
2 days. The mixture was poured into water and extracted with ethyl
acetate. The organic extracts were dried over MgSO.sub.4.
Evaporation and purification by flash chromatography (hexanes/ethyl
acetate 1/1) gave a white solid (5.6 g, 33 % yield): mp
99-101.degree. C.; MS m/e 343 (M+H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.09 (t, J=7.01, 3H), 1.18-1.22 (m, 2H),
1.78-1.83 (m, 2H), 3.0-3.05 (m, 2H), 3.56 (d, J=7.24 Hz, 2H),
3.68-3.72 (m, 3H), 3.97 (q, J=7.01 Hz, 2H), 4.7 (m, 1H), 6.98 (m,
2H), 7.53 (m, 2H), 7.76 (t, J=7.24 Hz, 1H);
[0464] Analysis for: C.sub.15H.sub.22FN.sub.2O.sub.5S Calc'd: C,
52.62; H, 6.48; N, 8.18 Found: C, 52.64; H, 6.48; N, 8.17
[0465] Step c) Ethyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)ace- tate
[0466] Trifluoroacetic acid (0.11 mL, 1.45 mmol) was added dropwise
into a cold (0.degree. C.) mixture of ethyl
2-({[4-(4-hydroxy-1-piperidinyl)phen- yl]sulfonyl}amino)acetate
(1.0 g, 2.9 mmol), dimethyl sulfoxide (7 mL), benzene (7 mL),
pyridine (0.23 mL, 2.9 mmol), and 1,3-dicyclohexylcarbodi- imide
(1.79 g, 8.7 mmol). The mixture was allowed to come to room
temperature, stirred for 20 hours, and then diluted with ethyl
acetate. The precipitated solid was filtered and discarded. The
filtrate was washed with water, and dried over MgSO.sub.4.
Evaporation and purification by flash chromatography (hexanes/ethyl
acetate 2/1) gave a white solid (820 mg, 82% yield): mp
90-92.degree. C.; MS m/e 341 (M+H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.1 (t, J=7.08 Hz, 3H), 2.41-2.44 (m, 2H),
3.6 (d, J=7.23 Hz, 2H), 3.76 (m, 2H), 4.0 (q, J=7.08 Hz, 2H), 7.05
(m, 2H), 7.58 (m, 2H), 7.8 (t, J=7.23 Hz, 1H);
[0467] Analysis for: C.sub.15H.sub.20FN.sub.2O.sub.5S Calc'd: C,
52.93; H, 2.92; N, 8.23 Found: C, 53.07; H, 5.93; N, 8.24
[0468] Step d) Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsul-
fonyl)-amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}aceta-
te
[0469] Acetic acid (0.61 mL, 10.7 mmol) was added dropwise into a
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
(1.32 g, 5.35 mmol), ethyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}am- ino)acetate (1.82,
5.35 mmol), and N,N-dimethylformamide (5 mL). The mixture was
stirred for 20 minutes and then, sodium triacetoxyborohydride (1.36
g, 6.42 mmol) was added, and the new mixture was stirred at room
temperature for 24 hours. The volatiles were removed in vacuo and
the residue was purified by HPLC reverse phase (YMC C18 column, 17%
MeOH: H.sub.2O/0.1% AcOH) to produce a white solid (2.4 g, 90%
yield): mp 105-107.degree. C.; MS m/e 571 (M+H).sup.+; .sup.1H NMR
(400 MHz, DMSO-d.sub.6): .delta. 1.09 (t, J=7.08, 3H), 1.25-1.35
(m, 2H), 1.8-1.85 (m, 2H), 2.6-2.7 (m, 3H), 2.82-2.91 (m, 5H), 3.56
(s, 3H), 3.8 (m, 2H), 3.97 (q, J=7.08 Hz, 2H), 4.5 (m, 1H), 6.8 (,
m, 2H), 7.0 (m, 3H), 7.18 (m, 1H), 7.56 (m, 2H);
[0470] Analysis for: C.sub.24H.sub.34N.sub.4O.sub.8S.sub.2.times.1
CH.sub.3CO.sub.2H Calc'd: C, 49.51; H, 6.07; N, 8.88 Found: C,
49.62; H, 6.23; N, 8.77
EXAMPLE 57
[0471] Methyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)a-
mino]-phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate
[0472] Step a) Methyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)ac- etate
[0473] A mixture of tert-butyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl- }amino)acetate (1.0,
2.72 mmol) and formic acid (95%, 10 mL) was stirred at 60.degree.
C. for 3 hours. The volatiles were then removed in vacuo and the
residue (847 mg) was taken in tetrahydrofuran (10 mL) and water
(0.2 mL). The mixture was cooled to 0.degree. C. and
(trimethylsilyl) diazomethane (2 M, 2 mL) was added dropwise. The
mixture was allowed to come to room temperature, stirred for 30
minutes, and then poured into water and extracted with ethyl
acetate. The organic extracts were dried over MgSO.sub.4.
Evaporation and purification by flash chromatography (hexanes/ethyl
acetate 2/1) gave a white solid (780 mg, 92% yield): mp
118-120.degree. C.; MS m/e 327 (M+H).sup.+; .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 2.43 (m, 4H), 3.53 (s, 3H), 3.59 (d, J=6.37
Hz, 2H), 3.76 (m, 2H), 7.05 9m, 2H), 7.59 (m, 2H), 7.82 (t, J=6.37
Hz, 1H);
[0474] Analysis for: C.sub.14H.sub.18N.sub.2O.sub.5S Calc'd: C,
51.52; H, 5.56; N, 8.58 Found: C, 51.52; H, 5.57; N, 8.51
[0475] Step b) Methyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsu-
lfonyl)-amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino}acet-
ate
[0476] Acetic acid (0.26 mL, 4.12 mmol) was added dropwise into a
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
(566 mg, 2.3 mmol), methyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}am- ino)acetate (750
mg, 0.23 mmol), and N,N-dimethylformamide (5 mL). The mixture was
stirred for 20 minutes and then, sodium triacetoxyborohydride (585
mg, 2.76 mmol) was added, and the new mixture was stirred at room
temperature for 24 hours. The volatiles were removed in vacuo and
the residue was purified by flash chromatography
(dichloromethane/methyl alcohol 8/1) to produce a white solid (1.15
mg, 90% yield): mp 123-125.degree. C.; MS m/e 571 (M+H).sup.+;
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.2-1.3 (m, 2H),
1.8-1.87 (m, 2H), 2.6-2.75 (m, 3H), 2.9-2.97 (m, 5H), 3.51 (, 3H),
3.57 (s, 2H), 3.8 (m, 2H), 4.5 (m, 1H), 6.8 (m, 1H), 7.0 (m, 3H),
7.2 (m, 1H), 7.57 (m, 2H);
[0477] Analysis for: C.sub.24H.sub.34N.sub.4O.sub.8S.sub.2.times.1
CH.sub.3CO.sub.2H Calc'd: C, 48.69; H, 5.88; N, 9.08 Found: C,
49.02; H, 5.87; N, 9.29
EXAMPLE 58
[0478] Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)am-
ino]-phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]amino}acetylcarbama-
te.
[0479] Step a) tert-Butyl
({[4-(4-oxopiperidin-1-yl)phenyl]sulfonyl}amino)- acetate
[0480] Trifluoroacetic acid (0.62 ml, 8.09 mmol) was added dropwise
into a cold (0.degree. C.) mixture of
tert-butyl-({[4-(4-hydroxypiperidin-1-yl)p-
henyl]sulfonylamino)acetate (6 g, 16.2 mmol),
1,3-dicyclohexylcarbodiimide (10 g, 48.6 mmol), pyridine (1.31 mL,
16.2 mmol), methyl sulfoxide (45 mL) and benzene (45 mL). The new
mixture was warmed up to room temperature and stirred for 18 hours,
diluted with ethyl acetate (100 mL), and the precipitated solid was
filtered and discarded. The organic filtrate was washed with water,
and dried over MgSO.sub.4. Evaporation and purification by flash
chromatography (hexanes/ethyl acetate 6/4) gave a white solid (5.65
g, 90% yield): MS m/e 369 (M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6
400 MHz) .delta. 1.29 (s, 9H), 2.42 (t, 4H), 3.46 (d, 2H), 3.72 (t,
4H), 7.07 (d, 2H), 7.56 (d, 2H), 7.58 (t, 1H).
[0481] Step b)
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)acetic acid
[0482] A mixture of
tert-butyl-({[4-(4-oxopiperidin-1-yl)phenyl]sulfonylam- ino)acetate
(1.75 g, 4.75 mmol) and formic acid (96%, 7 mL) was stirred at
60.degree. C. for 4 hours. The volatiles were removed in vacuo to
give a yellow solid (1.1 g, 74% yield): MS m/e 311 (M-H).sup.+;
.sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta. 2.45 (t, 4H), 3.58 (d,
2H), 3.80 (t, 4H), 7.17 (d, 2H), 7.64 (d, 2H), 7.72 (t, 1H), 12.7
(s, 1H).
[0483] Step c) Ethyl
2-({[4-(4-oxopiperidin-1-yl)phenyl]sulfonyl}amino)ace-
tylcarbamate
[0484] A mixture of
({[4-(4-oxopiperidin-1-yl)phenyl]sulfonyl}amino)acetic acid (0.312
g, 1.0 mmol), ethyl (tert-butylimino)methylenecarbamate (0.6 mL),
and tetrahydrofuran (3mL) was reflux for 3 hours. The volatiles
were removed in vacuo and the residue was purified by flash
chromatography (hexanes/ethyl acetate 6/4) to give a white solid
(0.17 g, 45% yield): MS m/e 382; (M-H).sup.+; .sup.1H NMR
(DMSO-d.sub.6 300 MHz) .delta. 1.25 (t, 3H), 2.50 (m, 4H), 3.4 (s,
2H), 3.81 (m, 4H), 4.18 (q, 2H), 7.15 (d, 2H), 7.65 (d, 2H), 10.65
(s, 1H).
[0485] Step d) Ethyl
2-{[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsul-
fonyl)-amino]phenyl}ethyl)
amino]piperidin-1-yl}phenyl)sulfonyl]amino}-ace- tylcarbamate.
[0486] A mixture of ethyl
2-({[4-(4-oxopiperidin-1-yl)phenyl]sulfonyl}amin- o)acetylcarbamate
(0.17 g, 0453 mmol) and N-{5-[(1R)-2-amino-1-hydroxyethy-
l]-2-hydroxyphenyl}methansulfonamide (0.115 g, 0.4674 mmol), sodium
triacetoxyborohydride (0.19 g, 0.90 mmol), acetic acid (0.1 mL) in
N,N-dimethylformamide (2.2 mL) was stirred at room temperature for
18 hours. The solvent was removed in vacuo and the residue was
purified by flash chromatography (methylene
chloride/methanol/ammonium hydroxide 8/2/0.001) to give a white
solid (0.17 g, 61% yield): mp 98-105.degree. C., MS m/e 614
(M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta. 1.17 (t,
3H), 1.29 (m, 2H), 1.88 (m, 2H), 2.67 (m, 3H), 2.90 (m, 5H), 3.80
(m, 4H), 4.07 (q, 2H), 4.48 (m, 1H), 6.82 (d, 1H), 6.99 (m, 3H),
7.16 (s, 1H), 7.51 (d, 2H);
[0487] Analysis for C.sub.25H.sub.35N.sub.5O.sub.9S.sub.2.times.1.0
CH.sub.3COOH.times.0.63 H2O Calc'd: C, 47.40; H, 5.78; N, 10.21
Found: C, 47.35; H, 6.02; N, 10.00.
EXAMPLE 59
[0488] tert-Butyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3[(methylsulfonyl)-
amino]-phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl](methoxycarbonyl)-
-amino]acetate
[0489] Step a) tert-Butyl
((methoxycarbonyl){[4-(4-oxopiperidin-1-yl)pheny-
l]-sulfonyl}amino)acetate
[0490] Sodium hydride (60% in mineral oil, 0.18 g, 4.6 mmol) was
added portionwise to a cold (0.degree. C.) mixture of
tert-butyl-({[4-(4-oxopip-
eridin-1-yl)phenyl]sulfonyl}amino)acetate (1.5 g, 4.07 mmol) and
N,N-dimethylformamide (8 mL).The mixture was stirred for 1 hour and
then methyl chloroformate (0.36 mL, 4.6 mmol) in
N,N-dimethylformamide (0.5 mL) was added dropwise. The new mixture
was warmed up to room temperature and stirred for 5 hours, poured
into water, neutralized to pH 7 with saturated aqueous bicarbonate
solution, and extracted with ethyl acetate. The organic extracts
were washed with brine, and dried over MgSO.sub.4. Evaporation and
purification by flash chromatography (hexanes/ethyl acetate 6/4)
gave a white solid (0.64 g, 37%): .sup.1H NMR (DMSO-d.sub.6 300
MHz) .delta. 1.41 (s, 9H), 2.52 (m, 4H), 3.63 (s, 3H), 3.81 (m,
4H), 4.41 (s, 2H), 7.12 (d, 2H), 7.79 (d, 2H).
[0491] Step b) tert-Butyl
[[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3[(methyls-
ulfonyl)-amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]-(methoxy-
carbonyl)-amino]acetate
[0492] This compound was prepared from tert-butyl
((methoxycarbonyl){[4-(4-
-oxopiperidin-1-yl)phenyl]sulfonyl}amino)acetate and
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
in substantially the same manner as described in Example 50, and
was obtained as a white solid (0.3 g, 62%): mp 110-115.degree. C.;
MS m/e 657 (M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta.
1.24 (m, 2H), 1.38 (s, 9H), 1.89 (m, 2H), 2.66 (m, 3H), 2.91 (s,
3H), 2.99 (m, 2H), 3.6 (s, 3H), 3.88 (m, 2H), 4.47 (s, 2H), 4.49
(m, 1H), 6.82 (s, 1H), 6.99 (m, 3H), 7.17 s, 1H), 7.67 (d,
2H.);
[0493] Analysis for
C.sub.28H.sub.40N.sub.4O.sub.10S.sub.2.times.0.8
CH.sub.3COOH.times.0.41H2O Calc'd: C, 50.34; H, 6.05; N, 7.83
Found: C, 50.06; H, 6.40; N, 7.52.
EXAMPLE 60
[0494]
[[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phen-
yl}-ethyl)amino]piperidin-1-yl}phenyl)sulfonyl](methoxycarbonyl)amino]acet-
ic acid
[0495] This compound was prepared from tert-butyl
[[(4-{4-[((2R)-2-hydroxy-
-2-{4-hydroxy-3[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}ph-
enyl)sulfonyl](methoxycarbonyl)amino]acetate in substantially the
same manner as described in Example 53, with one change; the
mixture was stirred at room temperature for 20 hours. The volatiles
were removed and the product was purified by reverse phase
chromatography to give a white solid (0.08 g, 45% yield): mp
60.degree. C., MS m/e 601 (M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6
400 MHz) .delta. 1.60 (m, 2H), 2.08 (m, 2H), 2.86 (m, 2H), 2.93 (s,
3H), 2.94 (m, 2H), 3.08 (m, 1H), 3.59 (s, 3H), 4.06 (m, 2H), 4.42
(s, 3H), 4.76 (m, 1H), 6.89 (d, 1H), 7.04 (m, 3H), 7.23 s, 1H),
7.70 (d, 2H);
[0496] Analysis for
C.sub.24H.sub.32N.sub.4O.sub.10S.sub.2.times.2.0
CF.sub.3COOH.times.0.63 H2O Calc'd: C, 40.00; H, 3.96; N, 6.66
Found: C, 37.84; H, 3.77; N, 5.87.
EXAMPLE 61
[0497] Ethyl
{(2,5-difluorobenzyl)[(4-[4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[-
(methyl-sulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]a-
mino}acetate
[0498] Step a)
N-(2,5-Difluorobenzyl)-4-fluorobenzenesulfonamide
[0499] A solution of 2,4-difluorobenzyl amine (9.5 g, 66.37 mmol)
in methylene chloride (15 mL) was added dropwise into a cold
(-10.degree. C.) mixture of 4-fluorobenzenesulfonyl chloride (15.6
g, 80 mmol), diisopropylethyl amine (18.1 mL, 104 mmol) and
methylene chloride (80 mL). The new mixture was warmed up to room
temperature, stirred for 4 hours, poured into water, acidified with
aqueous hydrochloric acid (2N), and extracted with methylene
chloride. The organic extracts were washed with brine, and dried
over MgSO.sub.4. Evaporation and purification by flash
chromatography (hexanes/ethyl acetate 8/2) gave an off white solid
(12.5 g, 63% yield): MS m/e 300 (M-H).sup.+; .sup.1H NMR
(DMSO-d.sub.6 400 MHz) .delta. 4.13 (d, 2H), 7.19 (m, 3H), 7.41 (d,
2H), 7.84 (d, 2H), 8.36 (t, 1H).
[0500] Step b)
N-(2,5-Difluorobenzyl)-4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl-
)-benzenesulfonamide
[0501] A mixture of
N-(2,5-difluorobenzyl)-4-fluorobenzenesulfonamide (12.1 g, 40.16
mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (9.9 ml) was heated at
65.degree. C. for 6 days. The product was purified by flash
chromatography (hexanes/ethyl acetate 7/3) to give a white solid
10.4 g, 62% yield), mp 135.degree. C.; MS m/e 425 (M+H).sup.+;
.sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta. 1.6 (m, 4H), 3.42 (m,
4H), 3.91 (s, 4H), 3.98 (d, 2H), 6.99 (d, 2H), 7.04 (m, 3H), 7.50
(d, 2H), 7.89 (t, 1H).
[0502] Step c)
N-(2,5-Difluorobenzyl)-4-(4-oxopiperidin-1-yl)benzenesulfon-
amide
[0503] N-(2,5-difluorobenzyl)-4-fluorobenzenesulfonamide (4.5 g,
10.60 mmol) was treated at -10.degree. C. with concentrated
hydrochloric acid (50 mL). The mixture was warmed up to room
temperature, stirred for 24 hours, neutralized with ammonium
hydroxide at 0.degree. C. and extracted with methylene chloride.
The organic extracts were washed with brine, and dried over
MgSO.sub.4. The solvent was removed in vacuo to give an off white
solid (4.1 g, 94% yield): mp 119.degree. C.; MS m/e 379
(M-H).sup.+; .sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta. 2.47 (m,
4H), 3.70 (m, 4H), 4.15 (d, 2H), 7.10 (d, 2H), 7.19 (m, 3H), 7.62
(d, 2H), 8.01 (t, 1H).
[0504] Step d) Ethyl
((2,5-difluorobenzyl){[4-(4-oxopiperidin-1-yl)phenyl]-
-sulfonyl}amino)acetate
[0505] A mixture of
N-(2,5-difluorobenzyl)-4-(4-oxopiperidin-1-yl)benzenes- ulfonamide
(2 g, 5.25 mmol), potassium carbonate (0.8 g, 5.78 mmol), ethyl
bromoacetate (0.64 mL, 5.78 mmol) and acetonitrile (20 mL) was
reflux for 18 hours. After cooling to room temperature the mixture
was poured into aqueous ammonium chloride and extracted with ethyl
acetate. The organic extracts were washed with brine, and dried
over MgSO.sub.4. Evaporation and purification by flash
chromatography (hexanes/ethyl acetate 6/4) gave a light yellow oil
(1.49 g, 60% yield): MS m/e 465 (M-H).sup.+; .sup.1H NMR
(DMSO-d.sub.6 400 MHz) .delta. 1.08 (t, 3H), 2.48 (m, 4H), 3.75 (m,
4H), 3.94 (q, 2H), 3.97 (s, 2H), 4.38 (s, 2H), 7.08 (d, 2H), 7.19
(m, 3H), 7.64 (d, 2H).
[0506] Step e) Ethyl
{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hyd-
roxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sul-
fonyl]amino}acetate
[0507] This compound was prepared from ethyl
((2,5-difluorobenzyl){[4-(4-o-
xopiperidin-1-yl)phenyl]sulfonyl}amino)acetate, and
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methansulfonamide
in substantially the same manner as described in example 7, step d,
with one change; the product was purified by reverse phase
chromatography and was obtained as a white solid ( 1.25 g, 49%
yield): mp 85-90.degree. C.; MS m/e 697 (M+H).sup.+; .sup.1H NMR
(DMSO-d.sub.6 400 MHz) .delta. 1.07, (t, 3H), 1.31 (m, 2H), 1.89 (m
2H), 2.67 (m, 2H), 2.70 (m, 1H), 2.91 (s, 3H), 2.94, (m, 2H), 3.91
(m, 1H), 3.94 (q, 2H), 3.95 (s, 2H), 4.36, (s, 2H), 4.51 (m, 1H),
6.83 (d, 1H), 6.99 (m, 3H), 7.19 (m, 4H), 7.55 (d, 2H);
[0508] Analysis for
C.sub.31H.sub.38F.sub.2N.sub.4O.sub.8S.sub.2.times.2.0 CH.sub.3COOH
Cald'd: C, 45.45, H, 4.36; N, 6.28 Found: C, 46.23; H, 4.38; N,
6.28.
EXAMPLE 62
[0509]
1-[4-({[(Butylamino)carbonyl]amino}sulfonyl)phenyl]-4-[((2R)-2-hydr-
oxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidine
[0510] Step a) 1-(3-Bromoisoxazol-5-yl)ethanone
[0511] A solution of 4-fluorobenzenesulfonyl chloride (76 g, 0.39
mol) in tetrahydrofuran (200 mL) was added slowly into a cold
(-40.degree. C.) saturated tetrahydrofuran/ammonia solution (200
mL). The resulting suspension was allowed to come to room
temperature and stirred for 20 hours. The suspension was filtered
and the solid washed with ethyl acetate. The organic filtrate was
concentrated in vacuo and the product was crystallized from ethyl
acetate/hexanes to give a white solid (63 g, 92% yield): MS m/e 174
(M-H).sup.+; .sup.1H NMR (DMSO-d.sub.6 300 MHz) .delta. 7.42, (m,
4H), 7.85 (m, 2H).
[0512] Step b)
4-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)benzenesulfonamide
[0513] A mixture of 1-(3-bromoisoxazol-5-yl)ethanone (5.3 g, 30.28
mmol) and 1,4-dioxa-8-azaspiro[4.5]decane (7.4 mL) was warmed at
65.degree. C. for 4 days. After cooling to room temperature, the
mixture was triturated with methylene chloride to give a white
solid (3.0 g, 33% yield): MS m/e 297 (M-H); .sup.1H NMR
(DMSO-d.sub.6 300 MHz) .delta. 1.69 (m, 4H), 3.22 (m, 4H), 3.80 (s,
4H), 7.04 (d, 2H), 7.60 (d, 2H).
[0514] Step c)
1-[4-({[(Butylamino)carbonyl]amino}sulfonyl)phenyl]-4-oxopi-
peridine
[0515] Sodium hydride (60% in mineral oil, 0.1 g, 2.5 mmol) was
added at room temperature into a mixture of
4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)b- enzenesulfonamide (0.5 g,
1.67 mmol) and tetrahydro furan (10 mL). After stirring for 18
hours, n-butyl isocyanate (0.28 mL, 2.5 mmol) was added, and
stirring was continued overnight. The mixture was cooled to
0.degree. C. and acidified with concentrated hydrochloric acid (7
mL). The new mixture was allowed to come to room temperature,
stirred for another 18 hours, neutralized with ammonium hydroxide
at ) .degree. C., and extracted with ethyl acetate. The organic
extracts were washed with brine, and dried over MgSO.sub.4.
Evaporation and purification by flash chromatography
(hexanes/methylene chloride/isopropyl alcohol 5/4/1) gave a white
solid (0.34 g, 57% yield): MS m/e 352 (M-H).sup.+; .sup.1H NMR
(DMSO-d.sub.6 300 MHz) .delta. 0.96, (t, 3H), 1.23 (m, 2H), 1.38,
(m, 2H), 2.46 (m, 2H), 2.98, (m, 4H), 3.84 (m, 4H), 6.40, (t, 1H),
7.15 (d, 2H), 7.78 (d, 2H), 10.21 (s, 1H).
[0516] Step d)
1-[4-({[(Butylamino)carbonyl]amino}sulfonyl)phenyl]-4-[((2R-
)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piper-
idine
[0517] This compound was prepared from
1-[4-({[(butylamino)carbonyl]amino}-
sulfonyl)phenyl]-4-oxopiperidine, and
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-
-hydroxyphenyl}methansulfonamide in substantially the same manner,
as described in Example 50, with one change; the product was
purified by reverse phase chromatography and was obtained as a
white solid (0.16 g, 23% yield): mp 100-102.degree. C., MS m/e 584
(M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta. 0.75, (t,
3H), 1.13 (m, 2H), 1.23 (m 2H), 1.44 (m, 2H), 1.93 (m, 2H), 2.79
(m, 2H), 2.85 (m, 2H), 2.87 (m, 2H), 2.90 (s, 3H), 3.04 (m, 1H),
3.86 (m, 2H), 4.66 (m, 1H), 6.85 (d, 1H), 6.93 (d, 2H), 7.04 (m,
1H), 7.18 (d, 1H), 7.56, (d, 2H);
[0518] Analysis for C.sub.25H.sub.37N.sub.5O.sub.7S.sub.2.times.2.0
CH.sub.3COOH.times.067 H.sub.2O Cald'd: C, 48.67; H, 6.48; N, 9.79
Found : C, 46.16; H, 6.62; N, 9.81.
EXAMPLE 63
[0519]
2-{(2,5-Difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(met-
hylsulfonyl)-amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfonyl]amino-
}acetic acid
[0520] Step a) tert-Butyl
2-((2,5-difluorobenzyl){[4-(4-oxo-1-piperidinyl)-
phenyl]-sulfonyl}amino)acetate
[0521] Sodium hydride (60% in mineral oil, 0.49 g, 12.27 mmol) was
added portionwise to a cold (0.degree. C.) mixture of
tert-butyl({[4-(4-oxopipe- ridin-1-yl)phenyl]sulfonyl}amino)acetate
(4.0 g, 10.85 mmol) and N,N-dimethylformamide (60 mL). The mixture
was stirred for 2 hours, and then 2,5-difluorobenzyl bromide (1.4
mL, 10.85 mmol) in N,N-dimethylformamide (5 mL) was added dropwise.
The new mixture was stirred at 0.degree. C. for 2 hours, poured
into aqueous ammonium chloride, and extracted with ethyl acetate.
The organic extracts were washed with brine, and dried over
MgSO.sub.4. Evaporation and purification by flash chromatography
(hexanes/ethyl acetate 6/4) gave a white solid (3.2 g, 60% yield):
MS m/e 495 (M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6 300 MHz) .delta.
1.38 (s, 9H), 2.45 (m, 4H), 3.78 (m, 4H), 3.85 (s, 2H), 4.2 (s,
2H), 7.15 (d, 2H), 7.20 (m, 3H), 7.74 (d, 2H).
[0522] Step b) tert-Butyl
2-{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-
-{4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phe-
nyl)-sulfonyl]amino}acetate
[0523] This compound was prepared from tert-butyl
2-((2,5-difluorobenzyl){-
[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)acetate and
N-{5-[(1R)-2-amino-1-hydroxyethyl]-2-hydroxyphenyl}methanesulfonamide
in substantially the same manner, as described in Example 50, and
was obtained as a white solid (2.9 g , 63% yield): MS m/e 725
(M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6 400 MHz) .delta. 1.27, (s,
9H), 1.29 (m, 2H), 1.88 (m 2H), 2.68 (m, 2H), 2.72 (m, 1H), 2.88
(m, 2H), 2.91 (s, 3H), 3.83 (m, 4H), 4.35 (s, 2H), 4.50 (m, 1H),
6.83 (d, 1H), 7.01 (m, 3H), 7.18 (m, 4H), 7.56 (d, 2H).
[0524] Step c)
2-{(2,5-Difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-
-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]-1-piperidinyl}phenyl)sulfony-
l]amino}acetic acid
[0525] This compound was prepared from tert-butyl
2-{(2,5-difluorobenzyl)[-
(4-{4-[((2R)-2-hydroxy-2-(4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)-
amino]-1-piperidinyl}phenyl)sulfonyl]amino}acetate in substantially
the same manner, as described in Example 53, with one change; the
mixture was stirred at room temperature for 20 hours. The volatiles
were removed and the product was purified by reverse phase
chromatography to give a white solid (1.44 g, 42% yield): mp
80-82.degree. C.; MS m/e 669 (M+H).sup.+; .sup.1H NMR (DMSO-d.sub.6
400 MHz) .delta. 1.62 (m, 2H), 2.11 (m, 2H), 2.85 (m, 2H), 2.94 (s,
3H), 2.96 (m, 1H), 3.11 (m, 1H), 3.34 (m, 1H), 3.88 (s, 2H), 3.99
(m, 2H), 4.37 (s, 2H), 4.79 (m, 1H), 6.01 (br, 1H), 6.90 (d, 1H),
7.05 (m, 3H), 7.18 (m, 3H), 7.21 (s, 1H), 7.59 (d, 2H), 8.58 (brs,
1H), 8.66 (brs, 1H), 8.74 (brs, 1H), 10.01 (brs, 1H);
[0526] Analysis for
C.sub.29H.sub.34F.sub.2N.sub.4O.sub.8S.sub.2.times.2.0
CF.sub.3COOH.times.0.73 H.sub.2O Calc'd: C, 43.52; H, 4.11; N, 6.15
Found: C, 42.95; H, 3.93; N, 6.08.
EXAMPLE 64
[0527] Ethyl
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)am-
ino]-phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}acet-
ate
[0528] step a) Ethyl
2-{4-[(4-fluorophenyl)sulfonyl]-1-piperazinyl}acetate
[0529] 4-Fluorobenzenesulfonyl chloride (10 g, 50.4 mmol) was added
into a cold (0.degree. C.) solution of
1-(ethoxycarbonylmethyl-piperazine) (5.64 mL, 50.4 mmol) and
N,N-diisopropylethylamine (9.13 mL, 55.4 mmol) in tetrahydrofuran
(100 mL) over a period of 20 minutes. The mixture was then stirred
at room temperature overnight. The mixture was concentrated and
water was added. The aqueous mixture was extracted with ethyl
acetate. The extracts were washed with water, dried with magnesium
sulfate. The extracts were concentrated to give an oil (16.38 g,
97% yield): .sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 1.13-1.18
(t, 3H), 2.55-2.60 (m, 4H), 2.86-2.90 (m, 4H), 3.22 (s, 2H),
4.01-4.06 (q, 2H), 7.46-7.51 (m, 2 H), 7.79-7.83 (m, 2H); MS m/z
331 (M+H).sup.+; Analysis for C.sub.14H.sub.19FN.sub.2O.sub.4S
Calc'd: C, 50.90; H, 5.80; N, 8.48; Found: C, 50.97; H, 5.87; N,
8.56.
[0530] step b) ethyl
2-(4-{[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}-1-pipe-
razinyl)acetate
[0531] A mixture of ethyl
2-{4-[(4-fluorophenyl)sulfonyl]-1-piperazinyl}ac- etate (8 g, 24.2
mmol), 4-piperidone hydrochloride monohydate (5.58 g, 36.3 mmol)
and potassium carbonate (10.0 g, 72.66 mmol) in 1,
3-dimethyl-3,4,5,6-tetrahydro-2 (1H)-pyrimidine (25 ML) and
acetonitrile was stirred at 75.degree. C. for 3 days. The mixture
was diluted with water and extracted with ethyl acetate. The
extract were washed with water and dried with MgSO.sub.4.
Evaporation and purification by flash column chromatography
(dichloromethane/ethyl acetate 1/1) gave a white solid (0.55 g, 6 %
yield): mp: 81-83.degree. C.; .sup.1H NMR (400 MHz, DMSO-d.sub.6):
.delta. 1.13-1.17 (t, 3H), 2.45-2.47 (m, 4H), 2.48-2.50 (m, 4H),
2.82-2.85 (m, 4H), 3.21 (s, 2H), 3.74-3.77 (m, 4H), 4.01-4.07 (q,
2H), 7.09-7.12 (d, 2H), 7.50-7.54 (d, 2H); MS m/z 409 M+.
[0532] step c) ethyl
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(methylsul-
fonyl)-amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-
-yl}acetate
[0533] The title compound was prepared from
N-{5-[(1R)-2-amino-1-hydroxyet-
hyl]-2-hydroxyphenyl}methanesulfonamide and ethyl
2-(4-{[4-(4-oxo-1-piperi-
dinyl)phenyl]sulfonyl}-1-piperazinyl)acetate in substantially the
same manner, as described in Example 50. The product was obtained
as a light yellow solid; mp: 91-92.degree. C.; .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 1.08-1.17 (t, 3H), 1.49-1.56 (m, 2H),
2.02-2.07 (m, 2H), 2.45-2.50 (m, 4H), 2.52-56 (m, 2H), 2.74-80 (m,
2H), 2.86-3.01 (m, 5H), 3.20 (s, 2H), 3.24-3.36 (m, 4H), 3.96-3.99
(d, 2H), 4.01-4.07 (q, 2H), 4.69-4.71 (m, 1H), 6.86-6.88 (d, 2H),
7.05-7.09 (m, 3H), 7.23-7.24 (m, 1H), 7.47-7.50 (d, 2H), 8.20 (brs,
4H); MS m/z 640 (M+H).sup.+; Analysis for
C.sub.28H.sub.41N.sub.5O.sub.8S.sub.2.times.1.0
F.sub.3CCO.sub.2H.times.0.18 CH.sub.2Cl.sub.2 Calc'd: C, 47.13; H,
5.55; N, 9.11; Found: C, 47.02; H, 5.75; N, 8.67.
EXAMPLE 65
[0534]
{4-[(4-{4-[((2R)-2-Hydroxy-2-{4-hydroxy-3-[(methylsulfonyl)amino]ph-
enyl}-ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]piperazin-1-yl}acetic
acid, sodium salt
[0535] A solution of ethyl
{4-[(4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-[(met-
hylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfonyl]-piper-
azin-1-yl}acetate (1.0 g, 1.02 mmol) and 1N aqueous sodium hydroxy
(4.1 mL, 4.1 mmol) in methyl alcohol-tetrahydrofuran (1/1) was
stirred at room temperature overnight. The solvent was removed in
vacuo and chased with benzene. Methyl alcohol (60 mL) was added and
the solid was isolated by filtration. The filtrate was then
concentrated to give a brown solid; mp 131.degree. C. (decomposed):
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.22-1.27 (m, 2H),
1.80-1.87 (m, 2H), 2.46-2.48 (m, 4H), 2.57-2.67 (m, 6H), 2.80-2.89
(m, 4H), 2.90-2.98 (m, 2H), 3.16 (s, 3H), 3.78-3.82 (m, 2H),
4.34-4.37 (m, 1H), 6.45-6.51 (m, 2H), 7.01-7.04 (d, 2H), 7.44-7.46
(d, 2H); MS m/z 612 (M+H).sup.+; Analysis for
C.sub.26H.sub.35N.sub.5O.su- b.8S.sub.2Na.sub.2.times.3.0
F.sub.3CCO.sub.2Na.times.0.47 H.sub.2O.times.1.0 CH.sub.3OH Calc'd:
C, 37.94; H, 4.04; N, 6.71; Found: C, 37.40; H, 3.98; N, 6.69.
EXAMPLE 66
[0536]
N-(2-Hydroxy-5-{(1R)-1-hydroxy-2-[(1-{4-[(4-methylpiperazin-1-yl)su-
lfonyl]phenyl}piperidin-4-yl)amino]ethyl}phenyl)methanesulfonamide
[0537] step a) 1-[(4-fluorophenyl)sulfonyl]-4-methylpiperazine
[0538] The title compound was prepared from 4-fluorobenzenesulfonyl
chloride, 1-methylpiperazine in substantially the same manner, as
described in example 9, step a. The product was obtained as an oil;
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.12 (s, 3H),
2.31-2.37 (m, 4 H), 2.85-2.92 (m, 4H), 7.46-7.52 (m, 2H), 7.76-7.82
(m, 2H); MS m/z 259 (M+H).sup.+; Analysis for
C.sub.11H.sub.15FN.sub.2O.sub.2S Calc'd: C, 51.15; H, 5.85; N,
10.84; Found: C, 51.18; H, 5.81; N, 10.90.
[0539] step b)
1-{4-[(4-methyl-1-piperazinyl)sulfonyl]phenyl}-4-piperidino- ne
[0540] The title compound was prepared from
1-[(4-fluorophenyl)sulfonyl]-4- -methylpiperazine and 4-piperidone
hydrochloride monohydate in substantially the same manner, as
described in Example 64. The product was obtained as a semi-solid:
.sup.1H NMR (300 MHz, DMSO-d.sub.6): .delta. 2.12 (s, 3H),
2.33-2.35 (m, 4H), 2.45-2.50 (m, 4H), 2.74-2.82 (m, 4H), 3.73-3.76
(m, 4H), 7.08-7.12 (d, 2H), 7.50-7.53 (m, 2H); MS m/z 338
(M+H).sup.+; Analysis for C.sub.16H.sub.23N.sub.3O.sub.3S Calc'd:
C, 56.95; H, 6.87; N, 12.45; Found: C, 57.03; H, 6.89; N,
12.38.
[0541] Step c)
N-(2-hydroxy-5-{(1R)-1-hydroxy-2-[(1-{4-[(4-methylpiperazin-
-1-yl)sulfonyl]phenyl}piperidin-4-yl)amino]ethyl}phenyl)methanesulfonamide
[0542] The title compound was prepared from
N-{5-[(1R)-2-amino-1-hydroxyet-
hyl]-2-hydroxyphenyl}methanesulfonamide, and
1-{4-[(4-methyl-1-piperazinyl- )sulfonyl]phenyl}-4-piperidinone in
substantially the same manner, as described in Example 50. The
product was obtained as a brown solid; mp: 89-91.degree. C.;
.sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 1.53-1.65 (m, 2H),
2.06-2.16 (m, 2H), 2.82-2.89 (m, 2H), 2.94 (s, 3H), 3.09-3.13 (m,
2H), 3.70 (brs, 2H), 4.01-4.05 (m, 2H), 4.76-4.79 (d, 2H), 6.11
(brs, 1H), 6.88-6.90 (d, 2H), 7.06-7.13 (m, 4H), 7.25 (s, 1H),
7.52-7.55 (d, 2H), 8.60 (brs, 1H); 8.58 (brs, 1H); 8.75 (s, 1H),
9.64 (brs, 1H), 10.00 (s, 1H); MS m/z 568 (M+H).sup.+; Analysis for
C.sub.25H.sub.37N.sub.5O.su- b.6S.sub.2.times.0.4 hexane.times.0.52
H.sub.2O Calc'd: C, 42.07; H, 4.93; N, 7.34; Found: C, 42.27; H,
4.60; N, 6.70.
EXAMPLE 67
[0543] tert-Butyl
{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{4-hydrox-
y-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}phenyl)sulfon-
yl]-amino}acetate
[0544] step a) tert-butyl
2-((2,5-difluorobenzyl){[4-(4-oxo-1-piperidinyl)-
-phenyl]sulfonyl}amino)acetate
[0545] Sodium hydride (60% in mineral oil, 0.12 g, 8.13 mmol) was
added portionwise to a cold (0.degree. C.) solution of tert-butyl
2-({[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)acetate (1.0 g,
2.71 mmol) in N,N-dimethylformamide (15 mL) under a nitrogen
atmosphere. After stirring for 1 hour a-bromo-2,5-difluorotoluene
(0.36 mL, 2.71 mmol) was added dropwise over a period of 10
minutes. The mixture was then stirred at 0.degree. C. for 2 hours.
The reaction was quenched with aqueous ammonium chloride to pH 5
and extracted with ethyl acetate. The extracts were washed with
water and dried with magnesium sulfate. The extracts were
concentrated to give a solid (1.3 g, 97% yield): .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 1.28 (s, 9H), 2.42-2.45 (m, 4H),
3.73-3.77 (m, 4H), 3.86 (s, 2H), 4.37 (s, 2H), 7.07-7.09 (d, 2H),
7.16-7.21 (m, 3H), 7.62-7.65 (d, 2H); MS m/z 495 (M+H).sup.+;
Analysis for C.sub.24H.sub.28F.sub.2N.sub.2O.sub.5S.times.Calc'd:
C, 58.29; H, 5.71; N, 5.66; Found: C, 58.55; H, 6.03; N, 5.44.
[0546] step b) tert-butyl
{(2,5-difluorobenzyl)[(4-{4-[((2R)-2-hydroxy-2-{-
4-hydroxy-3-[(methylsulfonyl)amino]phenyl}ethyl)amino]piperidin-1-yl}pheny-
l)sulfonyl]-amino}acetate
[0547] The title compound was prepared from
N-{5-[(1R)-2-amino-1-hydroxyet-
hyl]-2-hydroxyphenyl}methanesulfonamide and ethyl
2-((2,5-difluorobenzyl){-
[4-(4-oxo-1-piperidinyl)phenyl]sulfonyl}amino)acetate in
substantially the same manner, as described in Example 50. The
product was obtained as a white solid: .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 1.28 (s, 9H), 1.30-1.40 (m, 2H), 1.89-1.96
(m, 2H), 4.48-4.50 (m, 4H), 2.69-2.92 (m, 4H), 2.72 (s, 3H),
3.84-3.89 (m, 3H), 4.36 (s, 2H), 4.56-4.59 (m, 1H), 6.83-6.85 (m,
1H), 7.00-70.04 (m, 3 H), 7.14-7.23 (m, 4H), 7.57-7.60 (d, 2H),
8.21 (s, 1H); MS m/z 725 (M+H).sup.+; Analysis for
C.sub.33H.sub.42F.sub.2N.sub.4O.sub.8S.sub.2.times.1.0 HCO.sub.2H
Calc'd: C, 52.98; H, 5.75; N, 7.27; Found: C, 51.24; H, 5.77; N,
7.14.
* * * * *